Tricyclic pyridones and pyrimidones

ABSTRACT

Compounds with KRAS G12C inhibitory active are disclosed and methods of using the same to treat a cancer comprising a K-Ras G12C mutation.

REFERENCE TO SEQUENCE LISTING

This application incorporates by reference a Computer Readable Form(CRF) of a Sequence Listing in ASCII text format submitted with thisapplication, entitled 055745-502C05US_SequenceListing, was created onDec. 8, 2022, and is 8,196 bytes in size.

BACKGROUND

Embodiments herein relate to compounds and methods for the treatment ofRAS-mediated disease. In particular, embodiments herein relate tocompounds and methods for treating diseases such as cancer via targetingoncogenic mutants of the K-RAS isoform.

Ras proteins are small guanine nucleotide-binding proteins that act asmolecular switches by cycling between active GTP-bound and inactiveGDP-bound conformations. Ras signaling is regulated through a balancebetween activation by guanine nucleotide exchange factors (GEFs), mostcommonly son of sevenless (SOS), and inactivation by GTPase-activatingproteins (GAPs) such as neurofibromin or p120GAP. The Ras proteins playan important role in the regulation of cell proliferation,differentiation, and survival. Dysregulation of the Ras signalingpathway is almost invariably associated with disease. Hyper-activatingsomatic mutations in Ras are among the most common lesions found inhuman cancer. Most of these mutations have been shown to decrease thesensitivity of Ras to GAP stimulation and decrease its intrinsic GTPaseactivity, leading to an increase in the active GTP-bound population.Although mutation of any one of the three Ras isoforms (K-Ras, N-Ras, orH-Ras) has been shown to lead to oncogenic transformation, K-Rasmutations are by far the most common in human cancer. For example, K-Rasmutations are known to be often associated with pancreatic, colorectaland non-small-cell lung carcinomas. Similarly, H-Ras mutations arecommon in cancers such as papillary thyroid cancer, lung cancers andskin cancers. Finally, N-Ras mutations occur frequently inhepatocellular carcinoma.

There is a need for effective Ras inhibitors, which may provide a newclass of anticancer compounds. These and other advantages will beapparent to those skilled in the art based upon embodiments anddisclosures herein.

SUMMARY

In some aspects, embodiments disclosed herein relate to compounds ofFormula (I)

wherein:

X is S(O)_(p), wherein p is an integer from 0 to 2;

j is an integer from 0 to 2;

Z¹ and Z² are independently CR⁶ or N, with the proviso that at least oneof Z¹ or Z² is CR⁶ with R⁶ being a bond to L¹;

L¹ is linking group comprising at least one nitrogen atom;

E is an electrophilic moiety, wherein E is bound to L¹ via the at leastone nitrogen atom;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, alkoxy, aryl, heteroaryl, N-arylamino,N-aryl-N-alkylamino, aryloxy, and arylthio with the proviso that:

at least one R¹ is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy,arylthio, or heteroaryl, any of which is optionally substituted;

n is an integer from 1 to 3;

R² is selected from the group consisting of alkyl, alkylamino,dialkylamino alkylamidoalkyl, arylamidoalkyl, alkylsulfonamidoalkyl,arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl aminoalkyl,alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo,haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted;

m is an integer from 0 to 6;

R³, R⁴, and R⁵ are each independently selected from the group consistingof hydrogen alkyl, halo, alkoxy, aryl, and heteroaryl, any of which areoptionally substituted; and

R⁶ is selected from the group consisting of hydrogen, alkyl, haloalkyl,cyano, halo, alkoxy, aryl, heteroaryl, trifluoromethyl and bond to L¹.

In some aspects, embodiments herein relate to compounds according to anyone of the compound tables provided herein. In embodiments, the compoundtables are Table 2a, Table 3, Table 4, Table 5, Table 7, Table 8, Table11, 12, and Table 13.

In some aspects, embodiments herein relate to methods of treatingcancer. In embodiments, the cancer comprises a K-RAs G12 mutation. Inembodiments, the cancer is one or more of pancreatic, lung andcolorectal cancer. In embodiments, the pancreatic cancer is pancreaticductal adenocarcinoma (PDAC). In embodiments, the cancer is a CNScancer. In embodiments, the CNS cancer comprises a primary cancer. Infurther embodiments, the primary cancer comprises one or more of aglioma, meningioma, medulloblastoma, ganglioglioma, schwannoma, andcraniopharyngioma. In embodiments, the the glioma comprises one or moreof an astrocytoma, a glioblastoma, an oligodendroglioma, and aependymoma. In embodiments, the CNS cancer comprises a metastatic orsecondary cancer. In embodiments, the CNS cancer comprises a cancermetastasized from one or more of melanoma, breast cancer, colon cancer,kidney cancer, nasopharyngeal cancer, leukemia, lymphoma, myeloma, andother of unknown primary site. In embodiments, the CNS cancer comprisesa RAS associated cancer.

In some aspects, the compounds used in the methods provided herein mayinclude any of the compounds found in Table 2a, Table 3, Table 4, Table5, Table 7, Table 8, Table 11, 12, and Table 13

DETAILED DESCRIPTION I. General

Disclosed herein are potent and selective tricyclic quinazoline-2-onescompounds, which have been found to be useful as inhibitors of oncogenicmutants of RAS proteins. Among various advantages, the compoundsdisclosed herein are selective for oncogenic RAS mutants over wild-typeRAS proteins. Further, compounds disclosed herein may exhibitselectivity for oncogenic mutants of K-RAS over other mutated K-RASproteins, as well as mutants of the N-RAS and H-RAS isoforms. Inparticular, the compounds disclosed herein may exhibit selectivity forK-RAS, N-RAS, and H-RAS mutants having a common G12C mutation. Alsodisclosed herein are pharmaceutical compositions comprising thesecompounds, and their application in the treatment of disease, such ascancer. Methods of inhibition of oncogenic mutant K-RAS, N-RAS, andH-RAS activity are also provided, as well as methods for the treatmentof oncogenic mutant RAS-mediated diseases, especially those involvingelevated levels of oncogenic mutated RAS, in particular cancer.Accordingly, disclosed herein are uses of and methods of using thecompounds described herein to treat one or more of the cancers describedherein.

Disclosed herein is a class of compounds useful in treating oncogenicRAS-mediated disorders and conditions, defined by structural Formula(I):

wherein:

X is S(O)_(p), wherein p is an integer from 0 to 2;

j is an integer from 0 to 2;

Z¹ and Z² are independently CR⁶ or N, with the proviso that at least oneof Z¹ or Z² is CR⁶ with R⁶ being a bond to L¹; Z³ is O;

L¹ is linking group comprising at least one nitrogen atom;

E is an electrophilic moiety, wherein E is bound to L¹ via the at leastone nitrogen atom;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, alkoxy, aryl, heteroaryl, N-arylamino,N-aryl-N-alkylamino, aryloxy, and arylthio with the proviso that:

at least one R¹ is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy,arylthio, or heteroaryl, any of which is optionally substituted;

n is an integer from 1 to 3;

R² is selected from the group consisting of alkyl, alkylamino,alkylamidoalkyl, arylamidoalkyl, alkylsulfonamidoalkyl,arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl aminoalkyl,alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo,haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted;

m is an integer from 0 to 6;

R³, R⁴, and R⁵ are each independently selected from the group consistingof hydrogen alkyl, halo, alkoxy, aryl, and heteroaryl, any of which areoptionally substituted; and

R⁶ is selected from the group consisting of hydrogen, alkyl, haloalkyl,cyano, halo, alkoxy, aryl, heteroaryl, trifluoromethyl and bond to L¹.

Compounds according to the various embodiments disclosed herein possessuseful oncogenic mutant RAS inhibiting or modulating activity, and maybe used in the treatment or prophylaxis of a disease or condition inwhich oncogenic mutant RAS plays an active role. Thus, in a broadaspect, embodiments disclosed herein also provide pharmaceuticalcompositions comprising one or more compounds disclosed herein togetherwith a pharmaceutically acceptable carrier, as well as methods of makingand using the compounds and compositions. Embodiments disclosed hereinprovide methods for selectively inhibiting the RAS that are oncogenicmutants having the G12C mutation. In some embodiments, there areprovided methods for treating an oncogenic mutant K-RAS-mediateddisorder in a subject, comprising administering to the subject atherapeutically effective amount of a compound or pharmaceuticalcomposition according to the various embodiments disclosed herein.Related embodiments disclose the use of the compounds disclosed hereinas therapeutic agents, for example, in treating cancer and otherdiseases involving elevated levels of oncogenic mutant K-RAS. Thevarious embodiments disclosed herein also contemplate the use of thecompounds disclosed herein for use in the manufacture of a medicamentfor the treatment of a disease or condition ameliorated by theinhibition of oncogenic mutant K-RAS. In some such embodiments, thedisease or condition is cancer. Each of the aforementioned methods applyequally to the similar mutation in N-RAS and H-RAS bearing the G12Cmutation.

Compounds of the various embodiments disclosed herein may be selectiveamongst the RAS oncogenic mutant forms in various ways. For example,compounds described herein may be selective for G12C mutants of K-RAS,N-RAS, or H-RAS. In certain embodiments, compounds of the variousembodiments disclosed herein may be selective for K-RAS G12C over otherK-RAS mutants and Wild Type K-RAS. Likewise, compounds of variousembodiments disclosed herein may be selective for N-RAS and H-RASbearing the same G12C mutation. Some embodiments relate to the use ofthe compounds described herein to treat cell proliferative disorders,such as cancer, of the central nervous system (CNS). CNS cancer caninclude any cancer of the CNS including cancer of the brain, spinal cordand nerves. Such CNS cancers can include, for example, primary cancers(e.g., those that start in the brain) and secondary or metastatic CNScancers (those that do not start in the CNS but metastasize to the CNS).Any CNS cancer is contemplated including without limitation, forexample, gliomas (including astrocytomas and glioblastomas,oligodendrogliomas, ependymomas), meningiomas, medulloblastomas,gangliogliomas, schwannomas, and craniopharyngiomas. Any metastatic CNScancer is contemplated, including without limitation, a cancermetastasized to the CNS via metastases of melanoma, breast cancer, coloncancer, kidney cancer, nasopharyngeal cancer, lymphoma, myeloma,leukemia, and other cancers of unknown primary site.

The various embodiments disclosed herein also relate to methods ofinhibiting at least one RAS function comprising the step of contactingan oncogenic mutant RAS with a compound of Formula I or any of thecompounds from the tables, as described herein. The cell phenotype, cellproliferation, activity of the mutant RAS, change in biochemical outputproduced by active mutant RAS, expression of mutant RAS, or binding ofmutant RAS with a natural binding partner may be affected. Such methodsmay be embrace modes of treatment of disease, biological assays,cellular assays, biochemical assays, or the like.

IV. Definitions A. General Definitions

As used herein, the terms below have the meanings indicated.

When ranges of number values are disclosed, and the notation “from n₁ .. . to n₂” is used, where n₁ and n₂ are the numbers, then unlessotherwise specified, this notation is intended to include the numbersthemselves and the range between them. This range may be integral orcontinuous between and including the end values. By way of example, therange “from 2 to 6 carbons” is intended to include two, three, four,five, and six carbons, since carbons come in integer units. Compare, byway of example, the range “from 1 to 3 μM (micromolar),” which isintended to include 1 μM, 3 μM, and everything in between to any numberof significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass the recited value and the range which would be included byrounding up or down to that figure, taking into account significantfigures.

“A,” “an,” or “the” as used herein not only include aspects with onemember, but also include aspects with more than one member. Forinstance, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a cell” includes a plurality of such cells andreference to “the agent” includes reference to one or more agents knownto those skilled in the art, and so forth.

B. Chemical Definitions

The following chemical functional group definitions are provided to giveguidance in understanding their meaning and scope. Those skilled in theart will recognize that these functional groups are being used in amanner consistent with practice of the chemical arts. Any of thefollowing chemical functional groups may be optionally substituted asdefined below and each chemical functional group below may itself be anoptional substitution.

The term “acyl,” as used herein, alone or in combination, refers to acarbonyl (C═O) attached to an alkenyl, alkyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, or any other moiety were the atom attachedto the carbonyl is carbon. An “acetyl” group, which is a type of acyl,refers to a (—C(═O)CH₃) group. An “alkylcarbonyl” or “alkanoyl” grouprefers to an alkyl group attached to the parent molecular moiety througha carbonyl group. Examples of such groups include, without limitation,methylcarbonyl and ethylcarbonyl. Similarly, an “arylcarbonyl” or“aroyl” group refers to an aryl group attached to the parent molecularmoiety through a carbonyl group. Examples of such groups include,without limitation, benzoyl and naphthoyl. Accordingly, generic examplesof acyl groups include alkanoyl, aroyl, heteroaroyl, and so on. Specificexamples of acyl groups include, without limitation, formyl, acetyl,acryloyl, benzoyl, trifluoroacetyl and the like.

The term “alkenyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon radical having one or moredouble bonds and containing from 2 to 20 carbon atoms. In certainembodiments, the alkenyl may comprise from 2 to 6 carbon atoms, or from2 to 4 carbons, either of which may be referred to as “lower alkenyl.”The term “alkenylene” refers to a carbon-carbon double bond systemattached at two or more positions such as ethenylene (—CH═CH—). Alkenylcan include any number of carbons, such as C₂, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆,C₂₋₇, C₂₋₈, C₂₋₉, C₂₋₁₀, C₃, C₃₋₄, C₃₋₅, C₃₋₆, C₄, C₄₋₅, C₄₋₆, C₅, C₅₋₆,and C₆, and so on up to 20 carbon atoms. Alkenyl groups can have anysuitable number of double bonds, including, but not limited to, 1, 2, 3,4, 5 or more. Examples of alkenyl groups include, but are not limitedto, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl,isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl,1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl,1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted.Unless otherwise specified, the term “alkenyl” may include “alkenylene”groups.

The term “alkoxy,” as used herein, alone or in combination, refers to analkyl ether radical, wherein the term alkyl is as defined below. Alkoxygroups may have the general formula: alkyl-O—. As for alkyl group,alkoxy groups can have any suitable number of carbon atoms, such asC₁₋₆. Alkoxy groups include, for example, methoxy, ethoxy, propoxy,iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,pentoxy, hexoxy, and the like. The alkoxy groups can be furtheroptionally substituted as defined herein.

The term “alkyl,” as used herein, alone or in combination, (sometimesabbreviated Alk) refers to a straight-chain or branched-chain alkylradical containing from 1 to 20 carbon atoms. In certain embodiments,the alkyl may comprise from 1 to 10 carbon atoms. In furtherembodiments, the alkyl may comprise from 1 to 6 carbon atoms, or from 1to 4 carbon atoms. Alkyl can include any number of carbons, such asC₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₁₋₆, C₁₋₇, C₁₋₈, C₁₋₉, C₁₋₁₀, C₂₋₃, C₂₋₄, C₂₋₅,C₂₋₆, C₃₋₄, C₃₋₅, C₃₋₆, C₄₋₅, C₄₋₆ and C₅₋₆. For example, C₁₋₆ alkylincludes, but is not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc.Alkyl can also refer to alkyl groups having up to 20 carbons atoms, suchas, but not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl groupscan be substituted or unsubstituted. The term “alkylene,” as usedherein, alone or in combination, refers to a saturated aliphatic groupderived from a straight or branched chain saturated hydrocarbon attachedat two or more positions, such as methylene (—CH₂—). Unless otherwisespecified, the term “alkyl” may include “alkylene” groups. When thealkyl is methyl, it may be represented structurally as CH₃, Me, or justa single bond terminating with no end group substitution.

The term “alkylamino,” as used herein, alone or in combination, refersto an alkyl group attached to the parent molecular moiety through anamino group. Suitable alkylamino groups may be mono- or dialkylated,forming groups such as, for example, N-methylamino (—NHMe), N-ethylamino(—NHEt), N,N-dimethylamino (—NMe₂), N,N-ethylmethylamino (—NMeEt) andthe like. The term “aminoalkyl” refers to reverse orientation in whichthe amino group appears distal to the parent molecular moiety andattachment to the parent molecular moiety is through the alkyl group.For example, NH₂(CH₂)_(n)—describes an aminoalkyl group with a terminalamine at the end of an alkyl group attached to the parent molecularmoiety. The two terms alkylamino and aminoalkyl can be combined todescribe an “alkylaminoalkyl” group in which an alkyl group resides on anitrogen atom distal to the parent molecular moiety, such asMeNH(CH₂)_(n)—. In a similar manner, an aryl group, as defined herein,may combine in a similar fashion providing an arylaminoalkyl groupArNH(CH₂)_(n)—. For additional clarity nomenclature may be providedwhere the group that is attached to nitrogen is indicated so by use of“N-” in the name, such as N-arylaminoalkyl, which is understood to meanthat the aryl group is a substituent on the nitrogen atom of theaminoalkyl group, the alkyl being attached the parent molecular moiety.

The term “alkylidene,” as used herein, alone or in combination, refersto an alkenyl group in which one carbon atom of the carbon-carbon doublebond belongs to the moiety to which the alkenyl group is attached.

The term “alkylthio,” as used herein, alone or in combination, refers toan alkyl thioether (AlkS—) radical wherein the term alkyl is as definedabove and wherein the sulfur may be singly or doubly oxidized. Examplesof suitable alkyl thioether radicals include methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.Similarly, “arylthio” refers to arylthioether (ArS—) radical wherein theterm aryl is as defined herein and wherein the sulfur may be singly ordouble oxidized.

The term “alkynyl,” as used herein, alone or in combination, refers to astraight-chain or branched chain hydrocarbon radical having one or moretriple bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkynyl comprises from 2 to 6 carbon atoms. In furtherembodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term“alkynylene” refers to a carbon-carbon triple bond attached at twopositions such as ethynylene. Alkynyl can include any number of carbons,such as C₂, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₂₋₇, C₂₋₈, C₂₋₉, C₂₋₁₀, C₃, C₃₋₄,C₃₋₅, C₃₋₆, C₄, C₄₋₅, C₄₋₆, C₅, C₅₋₆, and C₆. Examples of alkynyl groupsinclude, but are not limited to, acetylenyl, propynyl, 1-butynyl,2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl,1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl,1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or1,3,5-hexatriynyl. Alkynyl groups can be substituted or unsubstituted.Unless otherwise specified, the term “alkynyl” may include “alkynylene”groups.

The terms “amido,” as used herein, alone or in combination, refer to anamino group as described below attached to the parent molecular moietythrough a carbonyl group. The term “C-amido” as used herein, alone or incombination, refers to a —C(═O)N(R)₂ group where is R as defined herein.The term “N-amido” as used herein, alone or in combination, refers toRC(═O)N(R′)— group, with R and R′ as defined herein. The term“acylamino” as used herein, alone or in combination, embraces an acylgroup attached to the parent moiety through an amino group. An exampleof an “acylamino” group is acetylamino (CH₃C(O)NH—).

The term “amino,” as used herein, alone or in combination, refers to—N(R)(R′) or —N⁺(R)(R′)(R″), wherein R, R′ and R″ are independentlyselected from the group consisting of hydrogen, alkyl, acyl,heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any ofwhich may themselves be optionally substituted.

The term “amino acid,” as used herein, alone or in combination, means asubstituent of the form —NRCH(R′)C(O)OH, wherein R is typicallyhydrogen, but may be cyclized with N (for example, as in the case of theamino acid proline), and R′ is selected from the group consisting ofhydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, amino, amido, cycloalkylalkyl, heterocycloalkylalkyl,arylalkyl, heteroarylalkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, thiol,thioalkyl, alkylthioalkyl, and alkylthio, any of which may be optionallysubstituted. The term “amino acid” includes all naturally occurringamino acids as well as synthetic analogues.

The term “aryl,” as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch rings may be attached together in a pendent manner or may be fused.The term “aryl” embraces aromatic radicals such as benzyl, phenyl,naphthyl, anthracenyl, phenanthryl, indanyl, indenyl, annulenyl,azulenyl, tetrahydronaphthyl, and biphenyl.

The term “arylalkenyl” or “aralkenyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkenyl group.

The term “arylalkoxy” or “aralkoxy,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkoxy group.

The term “arylalkyl” or “aralkyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term “arylalkynyl” or “aralkynyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkynyl group.

The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used herein,alone or in combination, refers to an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as benzoyl, naphthoyl,phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

The term aryloxy as used herein, alone or in combination, refers to anaryl group attached to the parent molecular moiety through an oxy.

The terms “benzo” and “benz,” as used herein, alone or in combination,refer to the divalent radical C₆H₄— derived from benzene. Examplesinclude benzothiophene and benzimidazole.

The term “carbamate,” as used herein, alone or in combination, refers toan ester of carbamic acid (—NHCOO—) which may be attached to the parentmolecular moiety from either the nitrogen or acid (oxygen) end, andwhich may be optionally substituted as defined herein.

The term “O-carbamyl” as used herein, alone or in combination, refers toa —OC(O)NRR′, group, with R and R′ as defined herein.

The term “N-carbamyl” as used herein, alone or in combination, refers toa ROC(O)NR′— group, with R and R′ as defined herein.

The term “carbonyl,” as used herein, when alone includes formyl[—C(═O)H] and in combination is a —C(═O)— group.

The term “carboxyl” or “carboxyl,” as used herein, refers to —C(═O)OH,O-carboxy, C-carboxy, or the corresponding “carboxylate” anion, such asis in a carboxylic acid salt. An “O-carboxy” group refers to a RC(═O)O—group, where R is as defined herein. A “C-carboxy” group refers to a—C(═O)OR groups where R is as defined herein.

The term “cyano,” as used herein, alone or in combination, refers to—CN.

The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein,alone or in combination, refers to a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl radical wherein each cyclicmoiety contains from 3 to 12 carbon atom ring members and which mayoptionally be a benzo fused ring system which is optionally substitutedas defined herein. In some embodiments, a cycloalkyl may comprise fromfrom 3 to 7 carbon atoms, or from 5 to 7 carbon atoms. Examples of suchcycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl,adamantyl and the like. “Bicyclic” and “tricyclic” as used herein areintended to include both fused ring systems, such asdecahydronaphthalene, octahydronaphthalene as well as the multicyclic(multicentered) saturated or partially unsaturated type. The latter typeof isomer is exemplified in general by, bicyclo[1.1.1]pentane, camphor,adamantane, and bicyclo[3.2.1]octane.

The term “electrophilic moiety,” as used herein, is used in accordancewith its plain ordinary chemical meaning and refers to a chemical groupthat is electrophilic. Exemplary electrophilic moieties include, withoutlimitation, unsaturated carbonyl containing compounds such asacrylamides, acrylates, unsaturated (i.e., vinyl) sulfones orphosphates, epoxides, and vinyl epoxides.

The term “ester,” as used herein, alone or in combination, refers to acarboxyl group bridging two moieties linked at carbon atoms(—CRR′C(═O)OCRR′—), where each R and R′ are independent and definedherein.

The term “ether,” as used herein, alone or in combination, typicallyrefers to an oxy group bridging two moieties linked at carbon atoms.“Ether” may also include polyethers, such as, for example,—RO(CH₂)₂O(CH₂)₂O(CH₂)₂OR′, —RO(CH₂)₂O(CH₂)₂OR′, —RO(CH₂)₂OR′, and—RO(CH₂)₂OH.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refersto a haloalkyl group attached to the parent molecular moiety through anoxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers toan alkyl radical having the meaning as defined above wherein one or morehydrogens are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl, trihaloalkyl and polyhaloalkyl radicals. Amonohaloalkyl radical, for one example, may have an iodo, bromo, chloroor fluoro atom within the radical. Dihalo and polyhaloalkyl radicals mayhave two or more of the same halo atoms or a combination of differenthalo radicals. Examples of haloalkyl radicals include fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. “Haloalkylene” refersto a haloalkyl group attached at two or more positions. Examples includefluoromethylene (—CFH—), difluoromethylene (—CF₂—), chloromethylene(—CHCl—) and the like.

The term “heteroalkyl,” as used herein, alone or in combination, refersto a stable straight or branched chain, or cyclic hydrocarbon radical,or combinations thereof, fully saturated or containing from 1 to 3degrees of unsaturation, consisting of the stated number of carbon atomsand from one to three heteroatoms selected from the group consisting ofO, N, and S, and wherein the nitrogen and sulfur atoms may optionally beoxidized and the nitrogen heteroatom may optionally be quaternized (i.e.bond to 4 groups). The heteroatom(s) O, N and S may be placed at anyinterior position of the heteroalkyl group. Up to two heteroatoms may beconsecutive, such as, for example, —CH₂NHOCH₃. The term heteroalkyl mayinclude ethers.

The term “heteroaryl,” as used herein, alone or in combination, refersto 3 to 7 membered unsaturated heteromonocyclic rings, or fusedpolycyclic rings, each of which is 3 to 7 membered, in which at leastone of the fused rings is unsaturated, wherein at least one atom isselected from the group consisting of O, S, and N. In some embodiments,a heteroaryl may comprise from 5 to 7 carbon atoms. The term alsoembraces fused polycyclic groups wherein heterocyclic radicals are fusedwith aryl radicals, wherein heteroaryl radicals are fused with otherheteroaryl radicals, or wherein heteroaryl radicals are fused withcycloalkyl radicals. Non-limiting examples of heteroaryl groups includepyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl,isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl,isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl,benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl,benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl,benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl,tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl,pyrrolopyridinyl and the like. Exemplary tricyclic heterocyclic groupsinclude carbazolyl, benzindolyl, phenanthrolinyl, dibenzofuranyl,acridinyl, phenanthridinyl, xanthenyl and the like.

Heteroaryl groups can include any number of ring atoms, such as, 5 to 6,3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12ring members. Any suitable number of heteroatoms can be included in theheteroaryl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4,1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups canhave from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring membersand from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3heteroatoms. The heteroaryl group can include groups such as pyrrole,pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine,pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers),thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Theheteroaryl groups can also be fused to aromatic ring systems, such as aphenyl ring, to form members including, but not limited to,benzopyrroles such as indole and isoindole, benzopyridines such asquinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine(quinazoline), benzopyridazines such as phthalazine and cinnoline,benzothiophene, and benzofuran. Other heteroaryl groups includeheteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groupscan be substituted or unsubstituted.

The heteroaryl groups can be linked via any position on the ring. Forexample, pyrrole includes 1-, 2- and 3-pyrrole, pyridine includes 2-, 3-and 4-pyridine, imidazole includes 1-, 2-, 4- and 5-imidazole, pyrazoleincludes 1-, 3-, 4- and 5-pyrazole, triazole includes 1-, 4- and5-triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes2-, 4-, 5- and 6-pyrimidine, pyridazine includes 3- and 4-pyridazine,1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-,5- and 6-triazine, 1,3,5-triazine includes 2-triazine, thiopheneincludes 2- and 3-thiophene, furan includes 2- and 3-furan, thiazoleincludes 2-, 4- and 5-thiazole, isothiazole includes 3-, 4- and5-isothiazole, oxazole includes 2-, 4- and 5-oxazole, isoxazole includes3-, 4- and 5-isoxazole, indole includes 1-, 2- and 3-indole, isoindoleincludes 1- and 2-isoindole, quinoline includes 2-, 3- and 4-quinoline,isoquinoline includes 1-, 3- and 4-isoquinoline, quinazoline includes 2-and 4-quinazoline, cinnoline includes 3- and 4-cinnoline, benzothiopheneincludes 2- and 3-benzothiophene, and benzofuran includes 2- and3-benzofuran.

Some heteroaryl groups include those having from 5 to 10 ring membersand from 1 to 3 ring atoms including N, O or S, such as pyrrole,pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine,pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene,furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole,quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine,cinnoline, benzothiophene, and benzofuran. Other heteroaryl groupsinclude those having from 5 to 8 ring members and from 1 to 3heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole,pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, andisoxazole. Some other heteroaryl groups include those having from 9 to12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole,quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine,cinnoline, benzothiophene, benzofuran and bipyridine. Still otherheteroaryl groups include those having from 5 to 6 ring members and from1 to 2 ring atoms including N, O or S, such as pyrrole, pyridine,imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan,thiazole, isothiazole, oxazole, and isoxazole.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” or“heterocyclyl” as used herein, alone or in combination, each refer to asaturated, partially unsaturated, or fully unsaturated monocyclic,bicyclic, or tricyclic heterocyclic radical containing at least oneheteroatom as ring members, wherein each heteroatom may be independentlyselected from the group consisting of nitrogen, oxygen, and sulfur. Incertain embodiments, a heterocycloalkyl may comprise from 1 to 4heteroatoms as ring members. In further embodiments, a heterocycloalkylmay comprise from 1 to 2 heteroatoms ring members. In some embodiments,a heterocycloalkyl may comprise from 3 to 8 ring members in each ring.In further embodiments, a heterocycloalkyl may comprise from 3 to 7 ringmembers in each ring. In yet further embodiments, a heterocycloalkyl maycomprise from 5 to 6 ring members in each ring. “Heterocycloalkyl” and“heterocycle” are intended to include sugars, sulfones, sulfoxides,N-oxides of tertiary nitrogen ring members, and carbocyclic fused andbenzo fused ring systems; additionally, both terms also include systemswhere a heterocycle ring is fused to an aryl group, as defined herein,or an additional heterocycle group. Examples of heterocycloalkyl groupsinclude aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl,dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl,dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl,dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, epoxy,isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl,tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. Theheterocycloalkyl groups may be optionally substituted unlessspecifically prohibited.

“Heterocycloalkyl” may refer to a saturated ring system having from 3 to12 ring members and from 1 to 5 heteroatoms of N, O and S. Theheteroatoms can also be oxidized, such as, but not limited to, S(O) andS(O)₂. Heterocycloalkyl groups can include any number of ring atoms,such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9,3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number ofheteroatoms can be included in the heterocycloalkyl groups, such as 1,2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to5, 3 to 4 or 3 to 5. The heterocycloalkyl group can include any numberof carbons, such as C₃₋₆, C₄₋₆, C₅₋₆, C₃₋₈, C₄₋₈, C₅₋₈, C₆₋₈, C₃₋₉,C₃₋₁₀, C₃₋₁₁, and C₃₋₁₂. The heterocycloalkyl group can include groupssuch as aziridine, azetidine, pyrrolidine, piperidine, azepane,diazepane, azocane, quinuclidine, pyrazolidine, imidazolidine,piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane,tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane,thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran),oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane,dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Theheterocycloalkyl groups can also be fused to aromatic or non-aromaticring systems to form members including, but not limited to, indoline,diazabicycloheptane, diazabicyclooctane, diazaspirooctane ordiazaspirononane. Heterocycloalkyl groups can be unsubstituted orsubstituted. For example, heterocycloalkyl groups can be substitutedwith C1 6 alkyl or oxo (═O), among many others. Heterocycloalkyl groupscan also include a double bond or a triple bond, such as, but notlimited to dihydropyridine or 1,2,3,6-tetrahydropyridine.

The heterocycloalkyl groups can be linked via any position on the ring.For example, aziridine can be 1- or 2-aziridine, azetidine can be 1- or2-azetidine, pyrrolidine can be 1-, 2- or 3-pyrrolidine, piperidine canbe 1-, 2-, 3- or 4-piperidine, pyrazolidine can be 1-, 2-, 3-, or4-pyrazolidine, imidazolidine can be 1-, 2-, 3- or 4-imidazolidine,piperazine can be 1-, 2-, 3- or 4-piperazine, tetrahydrofuran can be 1-or 2-tetrahydrofuran, oxazolidine can be 2-, 3-, 4- or 5-oxazolidine,isoxazolidine can be 2-, 3-, 4- or 5-isoxazolidine, thiazolidine can be2-, 3-, 4- or 5-thiazolidine, isothiazolidine can be 2-, 3-, 4- or5-isothiazolidine, and morpholine can be 2-, 3- or 4-morpholine.

When heterocycloalkyl includes 3 to 8 ring members and 1 to 3heteroatoms, representative members include, but are not limited to,pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene,thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine,isoxazolidine, thiazolidine, isothiazolidine, morpholine,thiomorpholine, dioxane and dithiane. Heterocycloalkyl can also form aring having 5 to 6 ring members and 1 to 2 heteroatoms, withrepresentative members including, but not limited to, pyrrolidine,piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine,imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine,isothiazolidine, and morpholine.

The term “hydrazinyl” as used herein, alone or in combination, refers totwo amino groups joined by a single bond, i.e., —N—N—. In general, thehydrazinyl group has optional substitution on at least one NH hydrogento confer stability.

The term “hydroxamic acid” or its ester as used herein, refers to—C(O)ON(R)O(R′), wherein R and R′ are as defined herein, or thecorresponding “hydroxamate” anion, including any correspondinghydroxamic acid salt.

The term “hydroxy,” as used herein, alone or in combination, refers toOH.

The term “hydroxyalkyl,” as used herein, alone or in combination, refersto a hydroxy group attached to the parent molecular moiety through analkyl group. “Hydroxyalkyl” or “alkylhydroxy” refers to an alkyl group,as defined above, where at least one of the hydrogen atoms is replacedwith a hydroxy group. As for the alkyl group, hydroxyalkyl oralkylhydroxy groups can have any suitable number of carbon atoms, suchas C₁₋₆. Exemplary C₁₋₄ hydroxyalkyl groups include, but are not limitedto, hydroxymethyl, hydroxyethyl (where the hydroxy is in the 1- or2-position), hydroxypropyl (where the hydroxy is in the 1-, 2- or3-position), hydroxybutyl (where the hydroxy is in the 1-, 2-, 3- or4-position), 1,2-dihydroxyethyl, and the like.

The term “imino,” as used herein, alone or in combination, refers toC═NR.

The term “iminohydroxy,” as used herein, alone or in combination, refersto C═N(OH) and it O-ether C═N—OR.

The term “isocyanato” refers to a —NCO group.

The term “isothiocyanato” refers to a —NCS group.

The phrase “linear chain of atoms” refers to the longest straight chainof atoms independently selected from carbon, nitrogen, oxygen andsulfur.

The term “linking group,” as used herein refers to any nitrogencontaining organic fragment that serves to connect the pyrimidine orpyridone core of the compounds disclosed herein to the electrophilicmoiety E, as defined herein. Exemplary linking groups includepiperazines, aminoalkyls, alkyl- or aryl-based diamines,aminocycloalkyls, amine-containing spirocyclics, any of which may beoptionally substituted as defined herein. In some embodiments, linkinggroups may comprise the substructure L-Q-L′-E wherein Q is a monocyclic4 to 7 membered ring or a bicyclic, bridged, or fused, or spiro 6-11membered ring, any of which optionally include one or more nitrogenatoms, E is the electrophilic group, L is bond, C₁₋₆ alkylene, —O—C₀₋₅alkylene, —S—C₀₋₅ alkylene, or —NH—C₀₋₅ alkylene, and for C₂₋₆ alkylene,—O—C₂₋₅ alkylene, —S—C₂₋₅ alkylene, and NH—C₂₋₅ alkylene, one carbonatom of any of the alkylene groups can optionally be replaced with O, S,or NH; and L′ is bond when Q comprises a nitrogen to link to E,otherwise L′ is NR, where R is hydrogen or alkyl.

The term “lower,” as used herein, alone or in combination, meanscontaining from 1 to and including 6 carbon atoms, or from 1 to 4 carbonatoms.

The term “mercaptyl” as used herein, alone or in combination, refers toan RS— group, where R is as defined herein.

The term “nitro,” as used herein, alone or in combination, refers to—NO₂.

The terms “oxy” or “oxa,” as used herein, alone or in combination, referto —O—.

The term “oxo,” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms.

The term “phosphoamide” as used herein, alone or in combination, refersto a phosphate group [(OH)₂P(═O)O—] in which one or more of the hydroxylgroups has been replaced by nitrogen, amino, or amido.

The term “phosphonate” as used herein, alone or in combination, refersto a group of the form ROP(OR′)(OR)O— wherein R and R′ are selected fromthe group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl,cycloalkyl, heteroaryl, and heterocycloalkyl, any of which maythemselves be optionally substituted. “Phosphonate” includes “phosphate[(OH)₂P(O)O—] and related phosphoric acid anions which may form salts.

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein,alone or in combination, refers to the —SO₃H group and its anion as thesulfonic acid is used in salt formation or sulfonate ester where OH isreplaced by OR, where R is not hydrogen, but otherwise is as definedherein, and typically being alkyl or aryl.

The term “sulfanyl,” as used herein, alone or in combination, refers to—S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to—S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to—S(O)₂—.

The term “N-sulfonamido” refers to a RS(═O)₂NR′— group with R and R′ asdefined herein.

The term “S-sulfonamido” refers to a —S(═O)₂NRR′, group, with R and R′as defined herein.

The terms “thia” and “thio,” as used herein, alone or in combination,refer to a —S— group or an ether wherein the oxygen is replaced withsulfur. The oxidized derivatives of the thio group, namely sulfinyl andsulfonyl, are included in the definition of thia and thio.

The term “thiol,” as used herein, alone or in combination, refers to an—SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl—C(═S)H and in combination is a —C(═S)— group.

The term “N-thiocarbamyl” refers to an ROC(═S)NR′— group, with R and R′as defined herein.

The term “O-thiocarbamyl” refers to a —OC(═S)NRR′, group with R and R′as defined herein.

The term “thiocyanato” refers to a —CNS group.

The term “trihalomethanesulfonamido” refers to a X₃CS(═O)₂NR— group withX is a halogen and R as defined herein.

The term “trihalomethanesulfonyl” refers to a X₃CS(═O)₂— group where Xis a halogen.

The term “trihalomethoxy” refers to a X₃CO— group where X is a halogen.

The term “trisubstituted silyl,” as used herein, alone or incombination, refers to a silicone group substituted at its three freevalences with groups as listed herein under the definition ofsubstituted amino. Examples include trimethylsilyl,tert-butyldimethylsilyl, triphenylsilyl and the like.

In embodiments of the invention, any one of the positions that isunderstood to have a hydrogen may also exist or understood to beisotopically enriched. In the compounds of this invention any atom notspecifically designated as a particular isotope is meant to representany stable isotope of that atom. Obtaining 100% deuteration at anyrelevant site of a compound in an amount of milligram or greater can bedifficult. Therefore, it is understood that some percentage of hydrogenmay still be present, even though a deuterium atom is specifically shownin a chemical structure. Thus, when a chemical structure contains a “D,”the compound represented by the structure is deuterium-enriched at thesite represented by “D.” Unless otherwise stated, when a position isdesignated specifically as “H” or “hydrogen,” the position is understoodto have hydrogen at its natural abundance isotopic composition. Alsounless otherwise stated, when a position is designated specifically as“D” or “deuterium,” the position is understood to have deuterium at anabundance that is at least 3340 times greater than the natural abundanceof deuterium, which is 0.015% (i.e., the term “D” or “deuterium”indicates at least 50.1% incorporation of deuterium). In embodiments, abenzene ring may be optionally exist as —C₆D₅, —C₆DH₄, —C₆D₂H₃, —C₆D₃H₂,and —C₆D₄H. In embodiments, a cyclohexyl group may optionally exist as—C₆D₁₁.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamido group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that said groupis absent. A “null” group occurring between two other group may also beunderstood to be a collapsing of flanking groups. For example, if in—(CH₂)_(x)G¹G²G³, the element G² were null, said group would become—(CH₂)_(x)G¹G³.

The term “optionally substituted” means the anteceding group or groupsmay be substituted or unsubstituted. Groups constituting optionalsubstitution may themselves be optionally substituted. For example,where an alkyl group is embraced by an optional substitution, that alkylgroup itself may also be optionally substituted. When substituted, thesubstituents of an “optionally substituted” group may include, withoutlimitation, one or more substituents independently selected from thefollowing groups or a particular designated set of groups, alone or incombination: alkyl, alkenyl, alkynyl, alkanoyl, heteroalkyl,heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, lowerperhaloalkyl, perhaloalkoxy, cycloalkyl, phenyl, aryl, aryloxy, alkoxy,haloalkoxy, oxo, acyloxy, carbonyl, carboxyl, alkylcarbonyl,carboxyester, carboxamido, cyano, hydrogen, halogen, hydroxy, amino,alkylamino, arylamino, amido, nitro, thiol, alkylthio, haloalkylthio,perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstitutedsilyl, N₃, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H, pyridinyl, thiophene,furanyl, carbamate, and urea. Particular subsets of optionalsubstitution include, without limitation: (1) alkyl, halo, and alkoxy;(2) alkyl and halo; (3) alkyl and alkoxy; (4) alkyl, aryl, andheteroaryl; (5) halo and alkoxy; and (6) hydroxyl, alkyl, halo, alkoxy,and cyano. Where an optional substitution comprises aheteroatom-hydrogen bond (—NH—, SH, OH), further optional substitutionof the heteroatom hydrogen is contemplated and includes, withoutlimitation optional substitution with alkyl, acyl, alkoxymethyl,alkoxyethyl, arylsulfonyl, alkyl sulfonyl, any of which are furtheroptionally substituted. These subsets of optional substitutions areintended to be merely exemplary and any combination of 2 to 5, or 2 to10, or 2 to 20 of the groups recited above up to all the group recitedabove and any subrange in between are contemplated. “Optionallysubstituted” may include any of the chemical functional groups definedhereinabove and throughout this disclosure. Two optional substituentsmay be joined together to form a fused five-, six-, or seven-memberedcarbocyclic or heterocyclic ring consisting of zero to threeheteroatoms, for example forming methylenedioxy or ethylenedioxy. Anoptionally substituted group may be unsubstituted (e.g., —CH₂CH₃), fullysubstituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) orsubstituted at a level anywhere in-between fully substituted andmonosubstituted (e.g., —CH₂CF₃).

The various optional substitutions need not be the same and anycombination of optional substituent groups may be combined. For example,a carbon chain may be substituted with an alkyl group, a halo group, andan alkoxy group. Where substituents are recited without qualification asto substitution, both substituted and unsubstituted forms areencompassed. Where a substituent is qualified as “substituted,” thesubstituted form is specifically intended. Additionally, different setsof optional substituents to a particular moiety may be defined asneeded; in these cases, the optional substitution will be as defined,often immediately following the phrase, “optionally substituted with.”

The term R or the term R′, appearing by itself and without a numberdesignation, unless otherwise defined, refers to a moiety selected fromthe group consisting of hydrogen, hydroxyl, halogen, alkyl, cycloalkyl,heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may beoptionally substituted. Each such R and R′ groups should be understoodto be optionally substituted as defined herein. Each incidence of R andR′ should be understood to be independent. Whether an R group has anumber designation or not, every R group, including R, R′ and R^(n)where n=(1, 2, 3, . . . n), every substituent, and every term should beunderstood to be independent of every other in terms of selection from agroup. Should any variable, substituent, or term (e.g. aryl,heterocycle, R, etc.) occur more than one time in a formula or genericstructure, its definition at each occurrence is independent of thedefinition at every other occurrence. Those of skill in the art willfurther recognize that certain groups may be attached to a parentmolecule or may occupy a position in a chain of elements from either endas written. Thus, by way of example only, an unsymmetrical group such as—C(O)N(R)— may be attached to the parent moiety at either the carbon orthe nitrogen.

Asymmetric centers, axial asymmetry (non-interchanging rotamers), or thelike may exist in the compounds of the various embodiments disclosedherein. Such chirality may be designated by the symbols “R” or “S,”depending on the configuration of substituents around the chiral carbonatom or the relevant axis. It should be understood that embodimentsencompasses all stereochemical isomeric forms, including diastereomeric,enantiomeric, and epimeric forms, d-isomers and l-isomers, and mixturesthereof. Individual stereoisomers of compounds can be preparedsynthetically from commercially available starting materials whichcontain chiral centers or by preparation of mixtures of enantiomericproducts followed by separation such as conversion to a mixture ofdiastereomers followed by separation or recrystallization,chromatographic techniques, direct separation of enantiomers on chiralchromatographic columns, or any other appropriate method known in theart. Starting compounds of particular stereochemistry are eithercommercially available or can be made and resolved by techniques knownin the art. Additionally, the compounds of the various embodimentsdisclosed herein may exist as geometric isomers. The various embodimentsdisclosed herein includes all cis, trans, syn, anti, entgegen (E), andzusammen (Z) isomers as well as the appropriate mixtures thereof.Additionally, compounds may exist as tautomers, including keto-enoltautomers; all tautomeric isomers are embraced by the embodimentsdisclosed herein.

Additionally, the compounds of the various embodiments disclosed hereincan exist in unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. In general,the solvated forms are considered equivalent to the unsolvated forms forthe purposes of the various embodiments disclosed herein.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered part of largersubstructure. A bond may be single, double, or triple unless otherwisespecified. A dashed line between two atoms in a drawing of a moleculeindicates that an additional bond may be present or absent at thatposition.

1. Salts of Compounds

The compounds disclosed herein can exist as pharmaceutically acceptablesalts, including acid addition salts. Suitable salts include thoseformed with both organic and inorganic acids. Such acid addition saltswill normally be pharmaceutically acceptable. However, salts ofnon-pharmaceutically acceptable salts may be of utility in thepreparation and purification of the compound in question. Basic additionsalts may also be formed and be pharmaceutically acceptable. For a morecomplete discussion of the preparation and selection of salts, refer toPharmaceutical Salts: Properties, Selection, and Use (Stahl, P.Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002). It is understood thateach of the compounds disclosed herein, and each embodiment of thecompounds set forth herein, include pharmaceutically acceptable salts ofsuch compounds.

The term “pharmaceutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds disclosed herein which arewater or oil-soluble or dispersible and pharmaceutically acceptable asdefined herein. The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting the appropriatecompound in the form of the free base with a suitable acid.Representative acid addition salts include acetate, adipate, alginate,L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate,formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate),lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, phosphonate, picrate, pivalate, propionate,pyroglutamate, succinate, sulfonate, tartrate, L-tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groupsin the compounds of the various embodiments disclosed herein can bequaternized with methyl, ethyl, propyl, and butyl chlorides, bromides,and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl,lauryl, myristyl, and stearyl chlorides, bromides, and iodides; andbenzyl and phenethyl bromides. Examples of acids which can be employedto form pharmaceutically acceptable addition salts include inorganicacids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, andorganic acids such as oxalic, maleic, succinic, and citric. Salts canalso be formed by coordination of the compounds with an alkali metal oralkaline earth ion. Hence, the various embodiments disclosed hereincontemplates sodium, potassium, magnesium, and calcium salts of thecompounds disclosed herein, and the like.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxyl group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of pharmaceutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

C. Treatment-Related Definitions

The term “disease” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder” and“condition” (as in medical condition), in that all reflect an abnormalcondition of the body or of one of its parts that impairs normalfunctioning and is typically manifested by distinguishing signs andsymptoms.

As used herein, the term “cancer” refers to all types of cancer,neoplasm or malignant tumors found in mammals (e.g., but not limited to,humans), including leukemia, lymphomas, carcinomas and sarcomas. Inembodiments, the cancer is a metastatic cancer. A metastatic cancer is acancer that has metastasized, e.g., the subject has developed asecondary malignant growth(s) at a distance from a primary (original)site of the cancer. The new, metastatic tumor is the same type of canceras the primary tumor. In embodiments, metastasis occurs via the centralnervous system and the compounds disclosed herein can ameliorate spreadof the cancer via the CNS.

Exemplary cancers that may be treated with a compound or method providedherein include cancer of the thyroid, endocrine system, the centralnervous system (“CNS,” e.g., brain, spine and nerves), breast, cervix,colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma,mesothelioma, ovary, sarcoma, stomach, uterus, Medulloblastoma,colorectal cancer, pancreatic cancer (specifically including pancreaticductal adenocarcinoma (PDAC)). Additional examples include, Hodgkin'sDisease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma,glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma,primary thrombocytosis, primary macroglobulinemia, primary brain tumors,cancer, malignant pancreatic insulanoma, malignant carcinoid, urinarybladder cancer, premalignant skin lesions, testicular cancer, lymphomas,thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tractcancer, malignant hypercalcemia, endometrial cancer, adrenal corticalcancer, neoplasms of the endocrine or exocrine pancreas, medullarythyroid cancer, medullary thyroid carcinoma, melanoma, colorectalcancer, papillary thyroid cancer, hepatocellular carcinoma, or prostatecancer.

The term “leukemia” refers broadly to progressive, malignant diseases ofthe blood-forming organs and is generally characterized by a distortedproliferation and development of leukocytes and their precursors in theblood and bone marrow. Leukemia is generally clinically classified onthe basis of (1) the duration and character of the disease-acute orchronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid(lymphogenous), or monocytic; and (3) the increase or non-increase inthe number abnormal cells in the blood-leukemic or aleukemic(subleukemic). Exemplary leukemias that may be treated with a compoundor method provided herein include, for example, acute nonlymphocyticleukemia, chronic lymphocytic leukemia, acute granulocytic leukemia,chronic granulocytic leukemia, acute promyelocytic leukemia, adultT-cell leukemia, aleukemic leukemia, a leukocythemic leukemia,basophylic leukemia, blast cell leukemia, bovine leukemia, chronicmyelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilicleukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia,hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia,acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia,lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia,megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia,myeloblastic leukemia, myelocytic leukemia, myeloid granulocyticleukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cellleukemia, multiple myeloma, plasmacytic leukemia, promyelocyticleukemia, Rieder cell leukemia, Schilling's leukemia, stem cellleukemia, subleukemic leukemia, or undifferentiated cell leukemia.

As used herein, the term “lymphoma” refers to a group of cancersaffecting hematopoietic and lymphoid tissues. It begins in lymphocytes,the blood cells that are found primarily in lymph nodes, spleen, thymus,and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma andHodgkin's disease. Hodgkin's disease represents approximately 15% of alldiagnosed lymphomas. This is a cancer associated with Reed-Stembergmalignant B lymphocytes. Non-Hodgkin's lymphomas (NHL) can be classifiedbased on the rate at which cancer grows and the type of cells involved.There are aggressive (high grade) and indolent (low grade) types of NHL.Based on the type of cells involved, there are B-cell and T-cell NHLs.Exemplary B-cell lymphomas that may be treated with a compound or methodprovided herein include, but are not limited to, small lymphocyticlymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zonelymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell)lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt'slymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, orprecursor B-lymphoblastic lymphoma. Exemplary T-cell lymphomas that maybe treated with a compound or method provided herein include, but arenot limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma,anaplastic large cell lymphoma, mycosis fungoides, and precursorT-lymphoblastic lymphoma.

The term “sarcoma” generally refers to a tumor which is made up of asubstance like the embryonic connective tissue and is generally composedof closely packed cells embedded in a fibrillar or homogeneoussubstance. Sarcomas that may be treated with a compound or methodprovided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma,melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adiposesarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma,botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma,Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing'ssarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma,granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmentedhemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma,immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma,Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymomasarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma,serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

The term “melanoma” is taken to mean a tumor arising from themelanocytic system of the skin and other organs. Melanomas that may betreated with a compound or method provided herein include, for example,acral-lentiginous melanoma, amelanotic melanoma, benign juvenilemelanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma,juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodularmelanoma, subungual melanoma, or superficial spreading melanoma.

The term “carcinoma” refers to a malignant new growth made up ofepithelial cells tending to infiltrate the surrounding tissues and giverise to metastases. Exemplary carcinomas that may be treated with acompound or method provided herein include, for example, medullarythyroid carcinoma, familial medullary thyroid carcinoma, acinarcarcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cysticcarcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolarcarcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinomabasocellulare, basaloid carcinoma, basosquamous cell carcinoma,bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogeniccarcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorioniccarcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma,cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum,cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma,carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epidermoidcarcinoma, carcinoma epitheliale adenoides, exophytic carcinoma,carcinoma ex ulcere, carcinoma fibrosum, gelatinifori carcinoma,gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare,glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma,hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma,hyaline carcinoma, hypernephroid carcinoma, infantile embryonalcarcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelialcarcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cellcarcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatouscarcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullarycarcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma,carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma,carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes,nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans,osteoid carcinoma, papillary carcinoma, periportal carcinoma,preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma,renal cell carcinoma of kidney, reserve cell carcinoma, carcinomasarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinomascroti, signet-ring cell carcinoma, carcinoma simplex, small-cellcarcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cellcarcinoma, carcinoma spongiosum, squamous carcinoma, squamous cellcarcinoma, string carcinoma, carcinoma telangiectaticum, carcinomatelangiectodes, transitional cell carcinoma, carcinoma tuberosum,tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

Cancers of the central nervous system (CNS) are contemplated fortreatment using the compounds described herein. CNS cancer can includeany cancer of the CNS including cancer of the brain, spinal cord andnerves. Such CNS cancers can include, for example, primary cancers(e.g., those that start in the brain) and secondary or metastaticcancers CNS cancers (those that do not start in the CNS but metastasizeto the CNS). Any CNS cancer is contemplated including withoutlimitation, those listed elsewhere herein and gliomas (includingastrocytomas and glioblastomas, oligodendrogliomas, ependymomas),meningiomas, medulloblastomas, gangliogliomas, schwannomas, andcraniopharyngiomas. Any metastatic CNS cancer is contemplated, includingwithout limitation, a cancer metastasized to the CNS from metastases ofmelanoma, breast cancer, colon cancer, kidney cancer, nasopharyngealcancer, and other of unknown primary site. Compounds described hereinhave the ability penetrate the CNS in order to treat CNS cancers, bothprimary and metastatic. Also, the treatments can include treating acancer originated in the CNS that metastasizes to other parts of the CNSor outside of the CNS. Thus, compounds disclosed herein can also preventor reduce metastatic pathways via the CNS.

“Ras associated cancer” (also referred to herein as “Ras relatedcancer”) refers to a cancer caused by aberrant Ras activity orsignaling. A “cancer associated with aberrant K-Ras activity” (alsoreferred to herein as “K-Ras related cancer”) is a cancer caused byaberrant K-Ras activity or signaling (e.g. a mutant K-Ras). K-Rasrelated cancers may include lung cancer, non-small cell lung cancer,breast cancer, leukemia, pancreatic cancer, colon cancer, colorectalcancer. Other cancers that are associated with aberrant activity of oneor more of Ras, K-Ras, H-Ras, N-Ras, mutant K-Ras (including K-Ras G12C,K-Ras G12V, K-Ras G13C, K-Ras G12D, K-Ras G13D mutants), mutant N-Ras,and mutant H-Ras are well known in the art, including G12C in both N-Rasand H-Ras, and determining such cancers are within the skill of a personof skill in the art.

The term “administer (or administering) a Ras inhibitor” meansadministering a compound that inhibits the activity or level (e.g.amount) or level of a signaling pathway of one or more Ras proteins(e.g. a Ras inhibitor, K-Ras inhibitor, N-Ras inhibitor, H-Rasinhibitor, mutant K-Ras inhibitor, K-Ras G12C inhibitor, K-Ras G12Vinhibitor, K-Ras G13C inhibitor, K-Ras G12D inhibitor, K-Ras G13Dinhibitor) to a subject. Administration may include, without beinglimited by mechanism, allowing sufficient time for the Ras inhibitor toreduce the activity of one or more Ras proteins or for the Ras inhibitorto reduce one or more symptoms of a disease (e.g. cancer, wherein theRas inhibitor may arrest the cell cycle, slow the cell cycle, reduce DNAreplication, reduce cell replication, reduce cell growth, reducemetastasis, or cause cell death). The term “administer (oradministering) a K-Ras inhibitor” means administering a compound thatinhibits the activity or level (e.g. amount) or level of a signalingpathway of one or more K-Ras proteins (K-Ras, mutant K-Ras, K-Ras G12C,K-Ras G12V, K-Ras G12D, K-Ras G13C, K-Ras G13D). In embodiments, theadministering does not include administration of any active agent otherthan the recited active agent.

The term “associated” or “associated with” in the context of a substanceor substance activity or function associated with a disease (e.g. Ras(e.g., human K-Ras or human H-Ras) activity, a protein associateddisease, a cancer associated with aberrant Ras activity, K-Rasassociated cancer, mutant K-Ras associated cancer, activated K-Rasassociated cancer, K-RasG12C associated cancer, K-Ras G12V associatedcancer, K-Ras G13C associated cancer, K-Ras G12D associated cancer,K-Ras G13D associated cancer) means that the disease (e.g. cancer) iscaused by (in whole or in part), or a symptom of the disease is causedby (in whole or in part) the substance or substance activity orfunction. For example, a cancer associated with aberrant Ras activity orfunction may be a cancer that results (entirely or partially) fromaberrant Ras activity or function (e.g. enzyme activity, protein-proteinbinding, signaling pathway) or a cancer wherein a particular symptom ofthe disease is caused (entirely or partially) by aberrant Ras activityor function. As used herein, what is described as being associated witha disease, if a causative agent, could be a target for treatment of thedisease. For example, a cancer associated with aberrant Ras activity orfunction or a Ras associated cancer, may be treated with a Ras modulatoror Ras inhibitor, in the instance where increased Ras activity orfunction (e.g., signaling pathway activity) causes the cancer. Forexample, a cancer associated with K-Ras G12C may be a cancer that asubject with K-Ras G12C is at higher risk of developing as compared to asubject without K-Ras G12C. For example, a cancer associated with K-RasG12V may be a cancer that a subject with K-Ras G12V is at higher risk ofdeveloping as compared to a subject without K-Ras G12V.

The term “Ras” refers to one or more of the family of human Ras GTPaseproteins (e.g. K-Ras, H-Ras, N-Ras). The term “K-Ras” refers to thenucleotide sequences or proteins of human K-Ras (e.g. human K-Ras4A(NP_203524.1), human K-Ras4B (NP_004976.2), or both K-Ras4A andK-Ras4B). The term “K-Ras” includes both the wild-type form of thenucleotide sequences or proteins as well as any mutants thereof. In someembodiments, “K-Ras” is wild-type K-Ras. In some embodiments, “K-Ras” isone or more mutant forms. The term “K-Ras” XYZ refers to a nucleotidesequence or protein of a mutant K-Ras wherein the Y numbered amino acidof K-Ras that has an X amino acid in the wildtype instead has a Z aminoacid in the mutant (e.g. K-Ras G12C has a G in wildtype protein but a Cin the K-Ras G12C mutant protein). In some embodiments K-Ras refers toK-Ras4A and K-Ras4B. In some embodiments, K-Ras refers to K-Ras4A. Insome embodiments, K-Ras refers to K-Ras4B (e.g., NM_004985.4 orNP_004976.2). In some embodiments, K-Ras refers to the protein including(e.g., consisting of) the amino acid sequence below or including thesequence below with one or more mutations (e.g., G12C, G12V, or G13C):

(SEQ ID NO: 1) MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQ GVDDAFYTLVREIRKHKEK

In some embodiments, K-Ras refers to the protein including (e.g.,consisting of) the amino acid sequence below or including (e.g.,consisting of) the sequence below with one or more mutations (e.g.,G12C, G12V, or G13C):

(SEQ ID NO: 2) MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQGVDDAFYTLVREIRKHKEKMSKDGKKKKKKSKTKCVIM

1 mteyklvvvg aggvgksalt iqliqnhfvd eydptiedsy rkqvvidget clldildtag 61qeeysamrdq ymrtgegflc vfainntksf edihhyregi krvkdsedvp mvlvgnkcdl 121psrtvdtkqa qdlarsygip fietsaktrq gvddafytlv reirkhkekm skdgkkkkkk 181sktkcvim (SEQ ID NO:3)

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic condition or disorderdescribed in the present disclosure. Such administration encompassesco-administration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofactive ingredients or in multiple, separate capsules for each activeingredient. In addition, such administration also encompasses use ofeach type of therapeutic agent in a sequential manner. In either case,the treatment regimen will provide beneficial effects of the drugcombination in treating the conditions or disorders described herein.

“K-RAS inhibitor” is used herein to refer to a compound that exhibits anIC₅₀ with respect to K-RAS activity of no more than about 100 mM andmore typically not more than about 50 mM, as measured in the K-RAS assaydescribed generally hereinbelow. “IC₅₀” is that concentration ofinhibitor that reduces the activity of an enzyme (e.g., K-RAS) tohalf-maximal level. Compounds of the various embodiments disclosedherein have been discovered to exhibit inhibition against oncogenicmutant K-RAS isoforms. In some embodiments, compounds will exhibit anIC₅₀ with respect to oncogenic mutant K-RAS of no more than about 10 mM;in further embodiments, compounds will exhibit an IC₅₀ with respect toK-RAS of no more than about 5 mM; in yet further embodiments, compoundswill exhibit an IC₅₀ with respect to K-RAS of not more than about 1 mM,as measured in the K-RAS assay described herein. In yet furtherembodiments, compounds will exhibit an IC₅₀ with respect to K-RAS of notmore than about 200 nM. Without being bound by theory, in someembodiments, the K-RAS inhibitor is an irreversible inhibitor by way ofcovalent bond formation to the cysteine at the G12C mutation site.

The phrase “therapeutically effective” is intended to qualify the amountof active ingredients used in the treatment of a disease or disorder.This amount will achieve the goal of reducing or eliminating the thedisease or disorder.

As used herein, reference to “treatment” of a subject is intended toinclude prophylaxis. The term “subject” means all mammals, includinghumans. Examples of subjects include humans, cows, dogs, cats, goats,sheep, pigs, and rabbits. In some embodiments, the subject is a human.

The term “prodrug” refers to a compound that is made active in vivothrough chemical reaction in vivo thereby releasing an active compound.Compounds disclosed herein can be modified to exist as prodrugs, asdescribed in Hydrolysis in Drug and Prodrug Metabolism: Chemistry,Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compoundsdescribed herein are structurally modified forms of the compound thatreadily undergo chemical changes under physiological conditions toprovide the active compound. Additionally, prodrugs can be converted tothe active compounds by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to a compoundwhen placed in a transdermal patch reservoir with a suitable enzyme orchemical reagent. Prodrugs are often useful because, in some situations,they may be easier to administer than the active compound, or parentdrug. They may, for instance, be bioavailable by oral administrationwhereas the parent drug is not. The prodrug may also have improvedsolubility in pharmaceutical compositions over the parent drug. A widevariety of prodrug derivatives are known in the art, such as those thatrely on hydrolytic cleavage or oxidative activation of the prodrug. Anexample, without limitation, of a prodrug is a compound which isadministered as an ester (the “prodrug”), which is then metabolicallyhydrolyzed to the carboxylic acid, as the active entity. Additionalexamples include peptidyl derivatives of a compound. The term“therapeutically acceptable prodrug,” refers to those prodrugs orzwitterions which are suitable for use in contact with the tissues ofsubjects without undue toxicity, irritation, and allergic response, arecommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use.

V. Compound Embodiments A. Genus I—General

In some embodiments, there are provided compounds of Formula (I):

wherein:

X is S(O)_(p), wherein p is an integer from 0 to 2;

j is an integer from 0 to 2;

Z¹ and Z² are independently CR⁶ or N, with the proviso that at least oneof Z¹ or Z² is CR⁶ with R⁶ being a bond to L¹;

L¹ is linking group comprising at least one nitrogen atom;

E is an electrophilic moiety, wherein E is bound to L¹ via the at leastone nitrogen atom;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, alkoxy, aryl, heteroaryl, N-arylamino,N-aryl-N-alkylamino, aryloxy, and arylthio with the proviso that:

-   -   at least one R¹ is aryl, N-arylamino, N-aryl-N-alkylamino,        aryloxy, arylthio, or heteroaryl, any of which is optionally        substituted;

n is an integer from 1 to 3;

R² is selected from the group consisting of alkyl, alkylamino,dialkylamino alkylamidoalkyl, arylamidoalkyl, alkylsulfonamidoalkyl,arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl aminoalkyl,alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo,haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted;

m is an integer from 0 to 6;

R³, R⁴, and R⁵ are each independently selected from the group consistingof hydrogen alkyl, halo, alkoxy, aryl, and heteroaryl, any of which areoptionally substituted; and

R⁶ is selected from the group consisting of hydrogen, alkyl, haloalkyl,cyano, halo, alkoxy, aryl, heteroaryl, trifluoromethyl and bond to L¹.

In one or more of the preceding embodiments, j is 1.

In one or more of the preceding embodiments, m is 0. In one or more ofthe preceding embodiments, m is 1.

In one or more of the preceding embodiments, Z¹ is CR⁶ with R⁶ being abond to L¹.

In one or more of the preceding embodiments, Z² is N.

In one or more of the preceding embodiments, L¹ is

wherein k is an integer from 0 to 4; and each R⁷ is independentlyselected from methyl, and cyanomethyl.

In one or more of the preceding embodiments, E is an acrylyl grouphaving optional substitution R:

wherein R is selected from the group consisting of fluorine, methyl, and—CH₂NR^(a)R^(b), wherein R^(a) and R^(b) are independently selected fromhydrogen or alkyl; or R^(a) and R^(b) combine to form a C₂-C₆ nitrogencontaining heterocycle.

B. Genus II—General Pyrimidone

In some embodiments, there are provided compounds of Formula (IIa):

wherein:

X is S(O)_(p), wherein p is an integer from 0 to 2;

j is an integer from 0 to 2;

L¹ is linking group comprising at least one nitrogen atom;

E is an electrophilic moiety, wherein E is bound to L¹ via the at leastone nitrogen atom;

each R¹ is an optional substitution selected from the group consistingof alkyl, cyano, cycloalkyl, halo, haloalkyl, trifluoromethyl, andalkoxy;

n is an integer from 0 to 2;

R² is selected from the group consisting of alkyl, alkylamino,dialkylamino alkylamidoalkyl, arylamidoalkyl, alkylsulfonamidoalkyl,arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl aminoalkyl,alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo,haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted;

m is an integer from 0 to 6;

R³, R⁴, and R⁵ are each independently selected from the group consistingof hydrogen alkyl, halo, alkoxy, aryl, and heteroaryl, any of which areoptionally substituted; and

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted.

In one or more of the preceding embodiments, j is 1.

In one or more of the preceding embodiments, m is 0. In one or more ofthe preceding embodiments, m is 1.

In one or more of the preceding embodiments, L¹ is

wherein k is an integer from 0 to 4; and each R⁷ is independentlyselected from methyl, and cyanomethyl.

In one or more of the preceding embodiments, E is an acrylyl grouphaving optional substitution R:

wherein R is selected from the group consisting of fluorine, methyl, and—CH₂NR^(a)R^(b), wherein R^(a) and R^(b) are independently selected fromhydrogen or alkyl; or R^(a) and R^(b) combine to form a C₂-C₆ nitrogencontaining heterocycle.

In one or more of the preceding embodiments, Ar creates axial asymmetry.

In one or more of the preceding embodiments, the compound is a singlerotamer.

In one or more of the preceding embodiments, Ar is:

wherein R⁹, R¹⁰, R¹¹, R¹², and R¹³ are each independently selected fromthe group consisting of hydrogen, halo, alkyl, alkoxy, haloalkyl,trifluoromethyl, cycloalkyl and any two adjacent R⁹, R¹⁰, R¹¹, R¹², andR¹³ together combine to form a further fused ring that is an aromaticring optionally comprising 1 to 3 heteroatoms independently selectedfrom N, O or S, the further fused ring being optionally substituted.

C. Genus III—Pyrimidone Unsubstituted Ring Fusion

In some embodiments, there are provided compounds of Formula (III):

wherein:

X is O, S(O)_(p) CR³R⁴, NR⁵, or C(O), wherein p is an integer from 0 to2;

L¹ is linking group comprising at least one nitrogen atom;

E is an electrophilic moiety, wherein E is bound to L¹ via the at leastone nitrogen atom;

each R¹ is an optional substitution independently selected from thegroup consisting of hydrogen, alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

n is an integer from 0 to 2;

R³, R⁴, and R⁵ are each independently selected from the group consistingof hydrogen alkyl, halo, alkoxy, aryl, and heteroaryl, any of which areoptionally substituted; and

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted.

In one or more of the preceding embodiments, X is O.

In one or more of the preceding embodiments, L¹ is

wherein k is an integer from 0 to 4; and each R⁷ is independentlyselected from methyl and cyanomethyl;

In one or more of the preceding embodiments, E is an acrylyl grouphaving optional substitution R:

wherein R is selected from the group consisting of fluorine, methyl, and—CH₂NR^(a)R^(b), wherein R^(a) and R^(b) are independently selected fromhydrogen or alkyl; or R^(a) and R^(b) combine to form a C₂-C₆ nitrogencontaining heterocycle.

In one or more of the preceding embodiments, optional substitutioncomprises monofluorination.

In one or more of the preceding embodiments, Ar creates axial asymmetry.

In one or more of the preceding embodiments, the compound is a singlerotamer.

In one or more of the preceding embodiments, Ar is:

wherein R⁹, R¹⁰, R¹¹, R¹², and R¹³ are each independently selected fromthe group consisting of hydrogen, halo, alkyl, alkoxy, haloalkyl,trifluoromethyl, cycloalkyl and any two adjacent R⁹, R¹⁰, R¹¹, R¹², andR¹³ together combine to form a further fused ring that is an aromaticring optionally comprising 1 to 3 heteroatoms independently selectedfrom N, O or S, the further fused ring being optionally substituted.

D. Genus VI—Pyrimidone Acrylate Functionalized

In some embodiments, there are provided compounds of Formula (VI):

wherein:

X is S(O)_(p), wherein p is an integer from 0 to 2;

j is an integer from 0 to 2;

L¹ is linking group comprising at least one nitrogen atom;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

n is an integer from 0 to 2;

R² is selected from the group consisting of alkyl, alkylamino,dialkylamino alkylamidoalkyl, arylamidoalkyl, alkylsulfonamidoalkyl,arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl aminoalkyl,alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo,haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted;

m is an integer from 0 to 6;

R³, R⁴, and R⁵ are each independently selected from the group consistingof hydrogen alkyl, halo, alkoxy, aryl, and heteroaryl, any of which areoptionally substituted;

R⁸ is selected from the group consisting of fluorine, methyl, and—CH₂NR^(a)R^(b), wherein R^(a) and R^(b) are independently selected fromhydrogen or alkyl; or R^(a) and R^(b) combine to form a C₂-C₆ nitrogencontaining heterocycle; and

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted.

E. Genus IX—Pyrimidone Heterocycle Linker Acrylate Functionalized

In some embodiments, there are provided compounds of Formula (IX):

wherein:

X is O, S(O)_(p) CR³R⁴, NR⁵, or C(O), wherein p is an integer from 0 to2;

j is an integer from 0 to 2;

G is selected from the group consisting of N, CH, and

wherein G¹ and G² are independently (CH₂)_(q), where q is 1 or 2;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted;

n is an integer from 0 to 2;

R² is selected from the group consisting of alkyl, alkylamino,dialkylamino alkylamidoalkyl, arylamidoalkyl, alkylsulfonamidoalkyl,arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl aminoalkyl,alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo,haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted;

m is an integer from 0 to 6;

R³, R⁴, and R⁵ are each independently selected from the group consistingof hydrogen alkyl, halo, alkoxy, aryl, and heteroaryl, any of which areoptionally substituted;

wherein k is an integer from 0 to 4; and each R⁷ is independentlyselected from methyl and cyanomethyl; and

wherein the acrylyl moiety linked to G is optionally substituted.

F. Genus XX—Pyridone Acrylate Functionalized Arylated

In some embodiments, there are provided compounds of Formula (XX):

wherein:

X is S(O)_(p), wherein p is an integer from 0 to 2;

j is an integer from 0 to 2;

L¹ is linking group comprising at least one nitrogen atom;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

n is an integer from 0 to 2;

R² is selected from the group consisting of alkyl, alkylamino,dialkylamino alkylamidoalkyl, arylamidoalkyl, alkylsulfonamidoalkyl,arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl aminoalkyl,alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo,haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted;

m is an integer from 0 to 6;

R³, R⁴, and R⁵ are each independently selected from the group consistingof hydrogen alkyl, halo, alkoxy, aryl, and heteroaryl, any of which areoptionally substituted;

R⁶ is is selected from the group consisting of hydrogen, alkyl,haloalkyl, cyano, halo, alkoxy, aryl, heteroaryl, and trifluoromethyl;

R⁸ is selected from the group consisting of fluorine, methyl, and—CH₂NR^(a)R^(b), wherein R^(a) and R^(b) are independently selected fromhydrogen or alkyl; or R^(a) and R^(b) combine to form a C₂-C₆ nitrogencontaining heterocycle; and

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted.

In one or more of the preceding embodiments, j is 1.

In one or more of the preceding embodiments, m is 0. In one or more ofthe preceding embodiments, m is 1.

In one or more of the preceding embodiments, L¹ is

wherein k is an integer from 0 to 4; and each R⁷ is independentlyselected from methyl and cyanomethyl;

In one or more of the preceding embodiments, Ar creates axial asymmetry.

In one or more of the preceding embodiments, the compound is a singlerotamer.

In one or more of the preceding embodiments, Ar is:

wherein R⁹, R¹⁰, R¹¹, R¹², and R¹³ are each independently selected fromthe group consisting of hydrogen, halo, alkyl, alkoxy, haloalkyl,trifluoromethyl, cycloalkyl and any two adjacent R⁹, R¹⁰, R¹¹, R¹², andR¹³ together combine to form a further fused ring that is an aromaticring optionally comprising 1 to 3 heteroatoms independently selectedfrom N, O or S, the further fused ring being optionally substituted.

In embodiments, there are provided compounds of formulas I, II, III, VI,IX, and XX characterized as being CNS penetrant as measured by aquantity in a rat brain model (when tested at 2 mg/kg after IV dosing)having a concentration value in the rat brain expressed in ng/g (ng ofcompound per gram of tissue). In embodiments, the concentration value inthe rat brain is at least 60 ng/g. In embodiments, the concentration isin a range from about 40 ng/g to about 300 ng/g. In embodiments, theconcentration is in a range from about 40 n/g to about 60 ng/g. Inembodiments, the concentration is in a range from 50 ng/g to about 300ng/g. In embodiments, the concentration is in a range from about 60 ng/gto about 300 ng/g. In embodiments, the concentration is in a range fromabout 100 ng/g to about 300 ng/g. In embodiments, the concentration isin a range from about 150 ng/g to about 300 ng/g. In embodiments, theconcentration is from about 150 ng/g to about 275 ng/g.

G. Compound Tables

TABLE 3 % CAF @ 10 uM, Ex. No. Structure MW 1 h Name 63

569.43 67 (S,E)-9-chloro-10-(3-chloro-5- fluorophenyl)-7-(4-(4,4-difluorobut-2-enoyl)-2- methylpiperazin-1-yl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 64

537.41 75 (S)-9-chloro-10-(3-chloro-5- fluorophenyl)-7-(4-(2-fluoroacryloyl)-2- methylpiperazin-1-yl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 65

587.42 3 (S)-9-chloro-10-(3-chloro-5- fluorophenyl)-7-(4-(2-fluoroacryloyl)-2- methylpiperazin-1-yl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 66

502.96 70 (S)-7-(4-acryloyl-2- methylpiperazin-1-yl)-9- chloro-10-(3,5-difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one67

552.97 91 (S,E)-9-chloro-7-(4-(4,4- difluorobut-2-enoyl)-2-methylpiperazin-1-yl)-10-(3,5- difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 68

646.17 87 (R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-3-((1-(2,2- difluoroethyl)piperidin-4- yl)methyl)-10-(4-fluorophenyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one69

664.16 96 (3R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-3-((1-(2,2- difluoroethyl)piperidin-4- yl)methyl)-10-(2,4-difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one70

665.14 94 (3R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-3-((1-(2,2- difluoroethyl)piperidin-4- yl)methyl)-10-(2,4-difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one71

518.03 87.8 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(isoquinolin-8-yl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 72

572.03 80.5 7-(7-acetyl-9-acryloyl-3,7,9- triazabicylco[3.3.1]nonan-3-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro-5H-[1,4]oxazino[2,3,4- ij]quinazolin-5-one 73

519.42 73 (S)-7-(4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(3-chloro-5- fluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 74

502.96 95.6 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,3- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 75

531.02 86.8 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,2-dimethyl- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 76

629.16 79.3 (3R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-3-((4- ethylpiperazin-1-yl)methyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 77

513.95 82 (2S)-1-acryloyl-4-(9-chloro- 10-(2,4-difluorophenyl)-5-oxo-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-7-yl)piperazine-2-carbonitrile 78

537.41 6.7 (S)-9-chloro-10-(4-chloro-3- fluorophenyl)-7-(4-(2-fluoroacryloyl)-2- methylpiperazin-1-yl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 79

587.42 92 (S,E)-9-chloro-10-(4-chloro-3- fluorophenyl)-7-(2-methyl-4-(4,4,4-trifluorobut-2- enoyl)piperazin-1-yl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 80

569.43 93.5 (S,E)-9-chloro-10-(4-chloro-3- fluorophenyl)-7-(4-(4,4-difluorobut-2-enoyl)-2- methylpiperazin-1-yl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 81

595.97 89 2-((2S)-4-(9-chloro-10-(2,4- difluorophenyl)-5-oxo-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-7-yl)-1-((E)-4,4,4-trifluorobut-2- enoyl)piperazin-2- yl)acetonitrile 82

537.41 85.8 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(5-chloro-2,4- difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 83

509.98 85.3 (S)-5-(7-(4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-5-oxo-2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-10-yl)-2- fluorobenzonitrile 84

579.04 43.8 7-(9-acryloyl-3,3-dioxido-3- thia-7,9-diazabicyclo[3.3.1]nonan-7- yl)-9-chloro-10-(2,4-difluorophenyl)-2,3-dihydro- 5H-[1,4]oxazino[2,3,4- ij]quinazolin-5-one85

542.02 60.3 (S)-5-(7-(4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-5-oxo-2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-10-yl)-2-fluoro- N-methylbenzamide 86

518.03 76.1 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(isoquinolin-5-yl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 87

614.15 82.4 (3R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-3-((1- methylpiperidin-4-yl)methyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 88

527.97 90.2 2-((2S)-1-acryloyl-4-(9-chloro-10-(2,4-difluorophenyl)-5-oxo- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-7-yl)piperazin-2- yl)acetonitrile 89

519.42 94.5 (S)-7-(4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(4-chloro-3- fluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 90

520.95 78.8 (S)-7-(4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(3,4,5- trifluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 91

632.14 94.8 (R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-3-((1-methylpiperidin- 4-yl)methyl)-10-(2,4,6-trifluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 92

632.14 96.7 (S)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-3-((1-methylpiperidin- 4-yl)methyl)-10-(2,4,6-trifluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 93

587.42 95 (S,E)-9-chloro-10-(3-chloro- 4-fluorophenyl)-7-(2-methyl-4-(4,4,4-trifluorobut-2- enoyl)piperazin-1-yl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 94

642.16 94.7 (3S)-3-(3-((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)propyl)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9- chloro-10-(2,4-difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one95

608.08 70.5 7-(9-acryloyl-7- (methylsulfonyl)-3,7,9-triazabicyclo[3.3.1]nonan-3- yl)-9-chloro-10-(2,4-difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one96

522.02 54 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(3-oxoisoindolin-4- yl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 97

642.16 96.5 (3R)-3-(3-((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)propyl)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9- chloro-10-(2,4-difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one98

519.42 86.4 (S)-7-(4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(3-chloro-4- fluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 99

516.99 87.2 (3R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-3-methyl-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 100

612.59 94 7-(4-acryloyl-6,6- dioxidohexahydrothieno[3,4-b]pyrazin-1(2H)-yl)-10-(2,4- difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 101

576.54 96.5 7-(9-acryloyl-7-oxo-3,9- diazabicyclo[3.3.1]nonan-3-yl)-10-(2,4-difluorophenyl)-9- (trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 102

516.99 95.4 8-((S)-4-acryloyl-2- methylpiperazin-1-yl)-10-chloro-11-(2,4- difluorophenyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4- ij]quinazolin-6-one 103

498.54 92.5 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-10-(2,4-difluorophenyl)-9-methoxy- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 104

527.97 94.4 2-((2S)-4-acryloyl-1-(9-chloro-10-(2,4-difluorophenyl)-5-oxo- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-7-yl)piperazin-2- yl)acetonitrile 105

522.02 18.9 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2-oxoindolin-4-yl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 106

537.41 45.2 (S)-7-(4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(4-chloro-2,6- difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 107

521.03 0 (S)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(1-methyl-1H- indazol-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 108

521.03 91.7 (R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(1-methyl-1H- indazol-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 109

660.15 96.9 (S)-3-(3-((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)propyl)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4,6- trifluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 110

660.15 96.6 (R)-3-(3-((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)propyl)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4,6- trifluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 111

588.95 95.2 (S,E)-9-chloro-7-(2-methyl-4- (4,4,4-trifluorobut-2-enoyl)piperazin-1-yl)-10- (2,4,6-trifluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 112

570.96 86.2 9-chloro-10-(2,4- difluorophenyl)-7-((S)-2-methyl-4-((E)-4,4,4- trifluorobut-2-enoyl)piperazin-1-yl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 113

520.95 21.7 9-chloro-10-(2,4- difluorophenyl)-7-((S)-4-(2-fluoroacryloyl)-2- methylpiperazin-1-yl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 114

496.57 92.8 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-10-(2,4-difluorophenyl)-9-ethyl-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 115

482.55 94.1 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-10-(2,4-difluorophenyl)-9-methyl-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 116

558 27.4 7-(6-acryloyl-1-oxo-2,6,9- triazaspiro[4.5]decan-9-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 117

527.97 75.6 7-(6-acryloyl-1-oxo-2,6,9- triazaspiro[4.5]decan-9-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 118

608.08 48.3 7-(4-acryloyl-6- (methylsulfonyl)octahydro-1H-pyrrolo[3,4-b]pyrazin-1- yl)-9-chloro-10-(2,4-difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one119

552.97 97.1 9-chloro-7-((S)-4-((E)-4,4- difluorobut-2-enoyl)-2-methylpiperazin-1-yl)-10-(2,4- difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 120

570.96 95.9 (S,E)-9-chloro-7-(4-(4,4- difluorobut-2-enoyl)-2-methylpiperazin-1-yl)-10- (2,4,6-trifluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 121

571.04 3.6 (2S)-4-(9-chloro-10-(2,4- difluorophenyl)-5-oxo-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-7-yl)-1-((E)-4-(dimethylamino)but-2- enoyl)piperazine-2-carbonitrile 122

629.16 80.9 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-3-((4- ethylpiperazin-1-yl)methyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 123

484.97 91.3 (R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2-fluorophenyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 124

484.97 96 (S)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2-fluorophenyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 125

531.94 94.5 (2S)-4-(9-chloro-10-(2,4- difluorophenyl)-5-oxo-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-7-yl)-1-(2-fluoroacryloyl)piperazine-2- carbonitrile 126

615.14 33.1 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-3-((4- methylpiperazin-1-yl)methyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 127

521.03 60 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(1-methyl-1H- indazol-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 128

543.97 62.7 7-(5-acryloyl-1-oxo-2,5,8- triazaspiro[3.5]nonan-8-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 129

547.04 95.3 7-(9-acryloyl-3-thia-7,9- diazabicyclo[3.3.1]nonan-7-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 130

547.02 94.5 (3R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-3- (methoxymethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 131

579.04 82.2 7-(4-acryloyl-6,6- dioxidohexahydrothieno[3,4-b]pyrazin-1(2H)-yl)-9-chloro- 10-(2,4-difluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 132

493.53 91.9 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-10-(2,4-difluorophenyl)-5-oxo-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazoline-9-carbonitrile 133

558 51.9 7-(5-acryloyl-2-methyl-1-oxo- 2,5,8-triazaspiro[3.5]nonan-8-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 134

530.97 85 7-(4- acryloylhexahydrofuro[3,4- b]pyrazin-1(2H)-yl)-9-chloro-10-(2,4-difluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 135

500.95 0 7-(3-acryloyl-3,6- diazabicyclo[3.1.1]heptan-6-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 136

483.97 89.4 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2-oxopyridin- 1(2H)-yl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 137

565.01 86.8 (R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-3-(methoxymethyl)-10- (2,4,6-trifluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 138

542.98 95.8 7-(9-acryloyl-7-oxo-3,9- diazabicyclo[3.3.1]nonan-3-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 139

502.96 94.8 7-((R)-4-acryloyl-3- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 140

502.96 90.6 7-((S)-4-acryloyl-3- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 141

536.52 95.7 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-10-(2,4-difluorophenyl)-9- (trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 142

547.41 94.7 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9- bromo-10-(2,4-difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one143

508.58 95.4 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-cyclopropyl-10-(2,4- difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 144

547.04 64.9 7-(4- acryloylhexahydrothieno[3,4-b]pyrazin-1(2H)-yl)-9-chloro- 10-(2,4-difluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 145

514.97 58 7-(5-acryloyl-2,5- diazabicyclo[4.2.0]octan-2-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 146

520.95 90.7 (S)-7-(4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4,6- trifluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 147

602.1 44.6 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9- chloro-10-(2,4-difluorophenyl)-3- (morpholinomethyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 148

534.96 95.9 (R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 1,1-dioxide 149

534.96 52.8 (S)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 1,1-dioxide 150

518.96 59.9 7-((R)-4-acryloyl-2- (hydroxymethyl)piperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 151

484.97 94.1 (S)-7-(4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(4-fluorophenyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 152

500.97 55.3 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2-fluoro-5- hydroxyphenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 153

517.43 55.7 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2-fluoro-5- hydroxyphenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 154

517.04 24 (R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(naphthalen-1-yl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 155

517.04 92.2 (S)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(naphthalen-1-yl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 156

516.99 0 7-((3S,5S)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 157

516.99 95 7-((3R,5S)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 158

502.96 64 7-((R)-4-acryloyl-2- methylpiperazin-1-yl)-9- chloro-10-(2,4-difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one159

521.03 37.2 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(5-methyl-1H- indazol-4-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 160

484.97 72.7 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2-fluorophenyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 161

527.97 1 (2R,5R)-4-acryloyl-1-(9- chloro-10-(2,4-difluorophenyl)-5-oxo-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-5- methylpiperazine-2- carbonitrile 162

534.98 39 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(5-(difluoromethyl)- 2-fluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 163

550.98 41.4 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9- chloro-10-(5-(difluoromethoxy)-2- fluorophenyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 164

488.94 95.1 7-(4-acryloylpiperazin-1-yl)-9- chloro-10-(2,4-difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one165

500.95 16.9 7-(6-acryloyl-3,6- diazabicyclo[3.1.1]heptan-3-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 166

502.92 65.5 7-(4-acryloyl-3-oxopiperazin- 1-yl)-9-chloro-10-(2,4-difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one167

534.98 69.8 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9- chloro-10-(2-(trifluoromethyl)phenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 168

500.97 30.6 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2-fluoro-6- hydroxyphenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 169

558.04 23.3 7-((S)-4-acryloyl-2-(azetidin- 1-ylmethyl)piperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 170

502.96 75.9 (S)-7-(4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,6- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 171

535.87 48.9 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,5- dichlorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 172

517.04 51.9 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(naphthalen-1-yl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 173

513.95 2.2 (2R)-4-acryloyl-1-(9-chloro- 10-(2,4-difluorophenyl)-5-oxo-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-7-yl)piperazine-2-carbonitrile 174

519.42 93.8 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(3-chloro-2- fluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 175

519.42 79.8 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(5-chloro-2- fluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 176

545.96 40.5 2-((2S)-4-(9-chloro-10-(2,4- difluorophenyl)-5-oxo-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-7-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile 177

548.99 93.5 (S)-7-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 1,1-dioxide 178

548.99 58.3 (R)-7-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 1,1-dioxide 179

502.96 96 (S)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 180

502.96 94.7 (R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 181

514.97 28.7 7-(5-acryloyl-2,5- diazabicyclo[2.2.2]octan-2-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 182

530.97 94.4 7-(9-acryloyl-3-oxa-7,9- diazabicyclo[3.3.1]nonan-7-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 183

531.07 45.3 7-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-10-(naphthalen-1-yl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 184

548.99 91.4 7-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 1,1-dioxide 185

581.05 93.3 7-((R)-4-acryloyl-2- ((methylsulfonyl)methyl)piperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 186

581.05 92.6 7-((R)-4-acryloyl-3- ((methylsulfonyl)methyl)piperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 187

581.05 83.7 7-((S)-4-acryloyl-3- ((methylsulfonyl)methyl)piperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 188

581.05 89.2 7-((S)-4-acryloyl-2- ((methylsulfonyl)methyl)piperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 189

516.99 93.8 7-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 190

534.96 88.2 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 1,1-dioxide 191

518.96 26.6 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 1-oxide 192

518.96 62.4 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 1-oxide 193

502.96 97 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9- chloro-10-(2,4-difluorophenyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4] ij]quinazolin-5-one

TABLE 4 % CAF @ 10 μM, Ex. Name Structure MW 1 h 3388-(9-acryloyl-7-oxo-3,9- diazabicyclo[3.3.1]nonan-3-yl)-11-(2,4-difluorophenyl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]oxazepino[2,3,4- ij]quinazolin-6-one

574.5 95.3 137 (R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-3-(methoxymethyl)-10-(2,4,6- trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

565.1 86.8 130 (3R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-3- (methoxymethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

547.1 94.5 99 (3R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-3- methyl-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

517.1 87.2 339 (R)-3-(3-((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)propyl)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4,6-trifluorophenyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

660.2 96.6 340 (S)-3-(3-((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)propyl)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4,6-trifluorophenyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

660.2 96.9 341 (3R)-3-(3-((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)propyl)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

642.3 96.5 342 (3S)-3-(3-((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)propyl)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

642.2 94.7 343 (S)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-3-((1-methylpiperidin-4- yl)methyl)-10-(2,4,6- trifluorophenyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

632.2 96.7 344 (R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-3-((1-methylpiperidin-4- yl)methyl)-10-(2,4,6- trifluorophenyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

632.2 94.8 345 (3R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-3-((1- methylpiperidin-4-yl)methyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

614.2 82.4 346 (3R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-3-((4- ethylpiperazin-1-yl)methyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

629.3 79.3 76 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-2,2- dimethyl-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

531.2 86.8 347 (3R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-3-((4-(2,2- difluoroethyl)piperazin-1- yl)methyl)-10-(2,4-difluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

665.2 82.5 348 (3R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-3-((1-(2,2- difluoroethyl)piperidin-4- yl)methyl)-10-(2,4-difluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

664.3 92 349 (R)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-3-((1-(2,2- difluoroethyl)piperidin-4- yl)methyl)-10-(4-fluorophenyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

646.2 94 350 (3S)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-10-(2,4-difluorophenyl)-3-((4- ethylpiperazin-1-yl)methyl)-9-(trifluoromethyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

663.3 95 351 (S)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-3-((4-ethylpiperazin-1- yl)methyl)-10-(2,4,6- trifluorophenyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

647.2 74 352 (3S)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-10-(2,4-difluorophenyl)-3- ((4-(oxetan-3- yl)piperazin-1-yl)methyl)-9-(trifluoromethyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

691.2 96 353 (3S)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-10-(2,4-difluorophenyl)-3-((1- ethylpiperidin-4-yl)methyl)-9-(trifluoromethyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

662.2 97 354 (3S)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10- (2,4-difluorophenyl)-3-((4- ethylpiperazin-1-yl)methyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin- 5(3H)-one

629.3 96 355 (3S)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10- (2,4-difluorophenyl)- 3-((4-(oxetan- 3-yl)piperazin-1-yl)methyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin- 5(3H)-one

657.3 96 356 (3S)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-3-((4-(2,2- difluoroethyl)piperazin-1- yl)methyl)-10-(2,4-difluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

665.3 95 19 (3S)-7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-3-((4-(2,2-difluoroethyl)piperazin-1- yl)methyl)-10-(2,4- difluorophenyl)-9-(trifluoromethyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

699.6 96

In embodiments, there is provided a compound selected from:

In embodiments, there are provided further compounds:

VI. General Synthetic Methods for Preparing Compounds

The following schemes can be used to practice the various embodimentsdisclosed herein. It will be understood that these schemes are merelyexemplary and that they provide ready access to core structures withvariable functionality.

VII. Modes of Administration

While it may be possible for the compounds disclosed herein to beadministered as the raw chemical, it is also possible to present them asa pharmaceutical composition (i.e., as a formulation). Accordingly,provided herein are pharmaceutical compositions which comprise one ormore of the compounds disclosed herein, or one or more pharmaceuticallyacceptable salts, esters, prodrugs, amides, or solvates thereof,together with one or more pharmaceutically acceptable carriers andoptionally one or more other therapeutic ingredients. The carrier(s)should be “acceptable” in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof. Proper formulation is dependent upon the route ofadministration chosen. Any of the well-known techniques, carriers, andexcipients may be used as suitable and as understood in the art; e.g.,in Remington's Pharmaceutical Sciences. The pharmaceutical compositionsdisclosed herein may be manufactured in any manner known in the art,e.g., by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orcompression processes.

The pharmaceutical compositions may include those suitable for oral,parenteral (including subcutaneous, intradermal, intramuscular,intravenous, intraarticular, and intramedullary), intraperitoneal,transmucosal, transdermal, rectal and topical (including dermal, buccal,sublingual and intraocular) administration although the most suitableroute may depend upon for example the condition and disorder of therecipient. The pharmaceutical composition may conveniently be presentedin unit dosage form and may be prepared by any of the methods well knownin the art of pharmacy. Typically, these methods include the step ofbringing into association a compound disclosed herein or apharmaceutically acceptable salt, ester, amide, prodrug or solvatethereof (“active ingredient”) with the carrier which constitutes one ormore accessory ingredients. In general, the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both and then,if necessary, shaping the product into the desired formulation.

Pharmaceutical compositions of the various embodiments disclosed hereinsuitable for oral administration may be presented as discrete units suchas capsules, cachets or tablets each containing a predetermined amountof the active ingredient; as a powder or granules; as a solution or asuspension in an aqueous liquid or a non-aqueous liquid; or as anoil-in-water liquid emulsion or a water-in-oil liquid emulsion. Theactive ingredient may also be presented as a bolus, electuary or paste.

Pharmaceutical compositions that can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated to provide slow or controlledrelease of the active ingredient therein. All formulations for oraladministration should be in dosages suitable for such administration.

The compounds disclosed herein may be formulated for parenteraladministration by injection, e.g., by bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored inpowder form or in a freeze-dried (lyophilized) condition requiring onlythe addition of the sterile liquid carrier, for example, saline orsterile pyrogen-free water, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets of the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

Dosage

The compounds disclosed herein may be administered orally or viainjection at a dose of from 0.1 to 500 mg/kg per day. A common doserange for adult humans is generally from 5 mg to 2 g/day. Tablets orother forms of presentation provided in discrete units may convenientlycontain an amount of one or more compounds which is effective at suchdosage or as a multiple of the same, for instance, units containing 5 mgto 500 mg, usually around 10 mg to 200 mg.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The compounds disclosed herein can be administered in various modes,e.g. orally, topically, or by injection. The precise amount of compoundadministered to a subject will be the responsibility of the attendantphysician. The specific dose level for any particular subject willdepend upon a variety of factors including the activity of the specificcompound employed, the age, body weight, general health, sex, diets,time of administration, route of administration, rate of excretion, drugcombination, the precise disorder being treated, and the severity of theindication or condition being treated. Also, the route of administrationmay vary depending on the condition and its severity.

In certain instances, it may be appropriate to administer at least oneof the compounds described herein (or a pharmaceutically acceptablesalt, ester, or prodrug thereof) in combination with another therapeuticagent. In any case, regardless of the disease, disorder or conditionbeing treated, the overall benefit experienced by the patient may simplybe additive of the two therapeutic agents or the patient may experiencea synergistic benefit.

In any case, the multiple therapeutic agents (at least one of which is acompound of the various embodiments disclosed herein) may beadministered in any order or even simultaneously. If simultaneously, themultiple therapeutic agents may be provided in a single, unified form,or in multiple forms (by way of example only, either as a single pill oras two separate pills). One of the therapeutic agents may be given inmultiple doses, or both may be given as multiple doses. If notsimultaneous, the timing between the multiple doses may be any durationof time ranging from a few minutes to four weeks.

VII. Methods of Treatment

Some embodiments relate to methods of using the compounds describedherein to treat cell proliferative disorders, such as cancer. The cancercan be any cancer, including those described herein. The cancer can be,for example, a RAS associated cancer. The treatments can include the useof combination treatments as described herein.

In some aspects of the embodiments, the cancer is a cancer of thecentral nervous system (CNS). CNS cancer can include any cancer of theCNS including cancer of the brain, spinal cord and nerves. Such CNScancers can include, for example, primary cancers (e.g., those thatstart in the brain) and secondary or metastatic CNS cancers (those thatdo not start in the CNS but metastasize to the CNS). The CNS cancer canbe a RAS associated cancer. Any CNS cancer is contemplated includingwithout limitation, for example, gliomas (including astrocytomas andglioblastomas, oligodendrogliomas, ependymomas), meningiomas,medulloblastomas, gangliogliomas, schwannomas, and craniopharyngiomas.Any metastatic CNS cancer is contemplated, including without limitation,a cancer metastasized to the CNS via metastases of melanoma, breastcancer, colon cancer, kidney cancer, nasopharyngeal cancer, lymphoma,myeloma, leukemia, and other cancers of unknown primary site. Someembodiments relate to treating, reducing or preventing metastasis of aCNS cancer, for example, to another region of the CNS and/or outside ofthe CNS.

As mentioned, embodiments herein provide methods for treating a RASassociated cancer, for example, a K-RAS-mediated disorders in a human oranimal subject in need of such treatment comprising administering tosaid subject an amount of a compound of the various embodimentsdisclosed herein effective to reduce or prevent said disorder in thesubject in combination with at least one additional agent for thetreatment of said disorder that is known in the art. In a relatedaspect, the various embodiments disclosed herein provides therapeuticcompositions comprising at least one compound of the various embodimentsdisclosed herein in combination with one or more additional agents forthe treatment of K-RAS-mediated disorders. In some such embodiments, theK-RAS-mediated disease is cancer and the K-RAS presents in an oncogenicmutated form.

Compounds disclosed herein may be useful in treating K-RAS-mediateddisease, disorders and conditions. In some embodiments, the compoundsdisclosed herein may be used in treating cancer, as disclosedhereinabove. In some such embodiments, the type of cancer may depend onpresentation of a particular type of oncogenic mutation of K-RAS. Forexample, in some embodiments oncogenic K-RAS mutations may be tied tohuman cancer of the pancreas, lung, and/or colon.

1. Combination Therapies

Compounds disclosed herein may be used in combination therapies. Forexample, the compounds disclosed herein may be used in combination withinhibitors of mammalian target of rapamycin (mTOR), insulin growthfactor 1 receptor (IGF1R), and combinations thereof. Such combinationtherapies may be particularly suited to certain cancer types such aslung cancer. See Molinas-Arcas et al. Sci. Trans. Med. 18 Sep. 201911:510 eaaw7999 at stm.sciencemag.org/content/11/510/eaaw7999. Compoundsdisclosed herein may be combined with modulators the ULK family ofproteins, which regulate autophagy. Other compounds of interest incombination therapy include inhibitors of SHP2. Other SHP2 inhibitorsinclude those disclosed in WO2016/203404, WO2018/136264, WO2018/057884,WO2019/067843, WO2019/183367, WO2016/203405, WO2019/051084,WO2018/081091, WO2019/165073, WO2017/216706, WO2018/218133,WO2019/183364, WO 2020061103, and WO2020061101. All references andpatent applications, including compositions, methods of using, andmethods of making compounds disclosed therein are incorporated herein byreference in their entirety.

In embodiments, compounds disclosed herein may be combined with an EGFRinhibitor. In embodiments, the EGFR inhibitor is selective for a mutantEGFR, including, without limitation, C797X, L718Q, G724S, S768I, G719X,L792X, G796X, T263P, A289D/V, G598V, and EGFRvIII high expression. Inembodiments, the combination therapy with EGFR agents tracked bymutation and indication are shown in Table 1 CT-1 below.

TABLE 1 CT-1 Mutation Indication EGFR agent mEGFR NSCLC osimertinibmEGFR NSCLC afatinib mEGFR NSCLC erlotinib mEGFR NSCLC gefitinib mEGFRNSCLC lazertinib mEGFR NSCLC nazartinib mEGFR NSCLC dacomitinib mEGFRNSCLC BLU-945 mEGFR NSCLC icotinib wtEGFR Esophageal/CRC cetuximabwtEGFR CRC paninitumab wtEGFR NSCLC amivantamab wtHER2/wtEGFR Breastcancer lapatinib wtHER2/wtEGFR Breast cancer neratinib wtEGFR NSCLCzorifertinib mEGFR NSCLC mobicertinib

EGFR inhibitors include those disclosed in U.S. Pat. Nos. 5,747,498,8,946,235, and 9,732,058, WO2002030926, US 20040048880, US20050165035,and WO2019067543. All patents and applications, including compositions,methods of using, and methods of making compounds disclosed therein areincorporated herein by reference in their entirety.

Other combination therapies based on target biomarkers are shown belowin Table 2: CT-2.

TABLE 2 CT-2 Cancer Combination Biomarker(s) Type Target Agent KRAS G12CSolid KRAS G12C AMG 510 tumors KRAS G12C Solid KRAS G12C MRTX849 tumorsKRAS G12C Solid KRAS G12C GDC-6036 tumors BRAF V600E CRC/ BRAF V600Eencorafenib NSCLC BRAF V600E CRC/ BRAF V600E dabrafenib NSCLC BRAF V600ECRC/ BRAF V600E encorafenib NSCLC and MEK and binimetinib BRAF V600ECRC/ BRAF V600E dabrafenib NSCLC and MEK and trametinib RB1 functionalSolid CDK4 and palbociclib tumors CDK6 RB1 functional Solid CDK4 andabemaciclib tumors CDK6 RB1 functional Solid CDK4 and ribociclib tumorsCDK6 RTK and/or RAS Driven Solid SHP2 TNO155 tumors RTK and/or RASDriven Solid SHP2 RMC-4630 tumors RTK and/or RAS Driven Solid SHP2JAB-3068 tumors RTK and/or RAS Driven Solid SHP2 JAB-3312 tumors RTKand/or RAS Driven Solid SHP2 RLY-1971 tumors RTK, RAS, BRAF, and/orSolid ERK ulixertinib MEK driven tumors RTK, RAS, BRAF, and/or Solid ERKASN007 MEK driven tumors RTK, RAS, BRAF, and/or Solid ERK LY3214996 MEKdriven tumors RTK, RAS, BRAF, and/or Solid ERK LTT462 MEK driven tumorsRTK, RAS, and/or BRAF Solid MEK trametinib tumors RTK, RAS, and/or BRAFSolid MEK binimetinib tumors RTK, RAS, and/or BRAF Solid MEK cobimetinibtumors RTK, RAS, and/or BRAF Solid MEK selumetinib tumors MET-drivenSolid MET capmatinib tumors MET-driven Solid MET crizotinib tumorsMET-driven Solid MET savolitinib tumors

The second agent of the pharmaceutical combination formulation or dosingregimen may have complementary activities to the compounds disclosedherein such that they do not adversely affect each other. The compoundsmay be administered together in a unitary pharmaceutical composition orseparately. In one embodiment a compound or a pharmaceuticallyacceptable salt can be co-administered with a cytotoxic agent to treatproliferative diseases and cancer.

The term “co-administering” refers to either simultaneousadministration, or any manner of separate sequential administration, ofa compound disclosed herein or a salt thereof, and a further activepharmaceutical ingredient or ingredients, including cytotoxic agents andradiation treatment. If the administration is not simultaneous, thecompounds are administered in a close time proximity to each other.Furthermore, it does not matter if the compounds are administered in thesame dosage form, e.g. one compound may be administered topically andanother compound may be administered orally.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

In certain embodiments, compositions of this invention are formulatedsuch that a dosage of between 0.01-100 mg/kg body weight/day of aninventive can be administered.

Typically, any agent that has activity against a disease or conditionbeing treated may be co-administered. Examples of such agents can befound in Cancer Principles and Practice of Oncology by V. T. Devita andS. Hellman (editors), 6^(th) edition (Feb. 15, 2001), LippincottWilliams & Wilkins Publishers. A person of ordinary skill in the artwould be able to discern which combinations of agents would be usefulbased on the particular characteristics of the drugs and the diseaseinvolved.

In one embodiment, the treatment method includes the co-administrationof a compound disclosed herein or a pharmaceutically acceptable saltthereof and at least one cytotoxic agent. The term “cytotoxic agent” asused herein refers to a substance that inhibits or prevents a cellularfunction and/or causes cell death or destruction. Cytotoxic agentsinclude, but are not limited to, radioactive isotopes (e.g., At²¹¹,I¹³¹, I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactiveisotopes of Lu); chemotherapeutic agents; growth inhibitory agents;enzymes and fragments thereof such as nucleolytic enzymes; and toxinssuch as small molecule toxins or enzymatically active toxins ofbacterial, fungal, plant or animal origin, including fragments and/orvariants thereof.

Exemplary cytotoxic agents can be selected from anti-microtubule agents,platinum coordination complexes, alkylating agents, antibiotic agents,topoisomerase II inhibitors, antimetabolites, topoisomerase Iinhibitors, hormones and hormonal analogues, signal transduction pathwayinhibitors, non-receptor tyrosine kinase angiogenesis inhibitors,immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A;inhibitors of fatty acid biosynthesis; cell cycle signalling inhibitors;HDAC inhibitors, proteasome inhibitors; and inhibitors of cancermetabolism.

“Chemotherapeutic agent” includes chemical compounds useful in thetreatment of cancer. Examples of chemotherapeutic agents includeerlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®,Millennium Pharm.), disulfiram, epigallocatechin gallate,salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol,lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca),sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinibmesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis),oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin,Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016,Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib (NEXAVAR®, BayerLabs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents suchas thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (includingtopotecan and irinotecan); bryostatin; callystatin; CC-1065 (includingits adozelesin, carzelesin and bizelesin synthetic analogs);cryptophycins (particularly cryptophycin 1 and cryptophycin 8);adrenocorticosteroids (including prednisone and prednisolone);cyproterone acetate; 5α-reductases including finasteride anddutasteride); vorinostat, romidepsin, panobinostat, valproic acid,mocetinostat dolastatin; aldesleukin, talc duocarmycin (including thesynthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; asarcodictyin; spongistatin; nitrogen mustards such as chlorambucil,chlomaphazine, chlorophosphamide, estramustine, ifosfamide,mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard;nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine,nimustine, and ranimnustine; antibiotics such as the enediyneantibiotics (e.g., calicheamicin, especially calicheamicin γ1I andcalicheamicin ω1I (Angew Chem. Intl. Ed. Engl. 1994 33:183-186);dynemicin, including dynemicin A; bisphosphonates, such as clodronate;an esperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antibiotic chromophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN®(doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL(paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE®(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), andTAXOTERE® (docetaxel, doxetaxel; Sanofi-Aventis); chlorambucil; GEMZAR®(gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinumanalogs such as cisplatin and carboplatin; vinblastine; etoposide(VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE®(vinorelbine); novantrone; teniposide; edatrexate; daunomycin;aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomeraseinhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such asretinoic acid; and pharmaceutically acceptable salts, acids andderivatives of any of the above.

Chemotherapeutic agent also includes (i) anti-hormonal agents that actto regulate or inhibit hormone action on tumors such as anti-estrogensand selective estrogen receptor modulators (SERMs), including, forexample, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene,droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene,LY117018, onapristone, and FARESTON® (toremifine citrate); (ii)aromatase inhibitors that inhibit the enzyme aromatase, which regulatesestrogen production in the adrenal glands, such as, for example,4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate),AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR®(vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole;AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide,bicalutamide, leuprolide and goserelin; buserelin, triptorelin,medroxyprogesterone acetate, diethylstilbestrol, premarin,fluoxymesterone, all transretinoic acid, fenretinide, as well astroxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) proteinkinase inhibitors; (v) lipid kinase inhibitors; (vi) antisenseoligonucleotides, particularly those which inhibit expression of genesin signaling pathways implicated in aberrant cell proliferation, suchas, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGFexpression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors;(viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®,LEUVECTIN®, and VAXID®; PROLEUKIN®, rIL-2; a topoisomerase 1 inhibitorsuch as LURTOTECAN®; ABARELIX® rmRH; and (ix) pharmaceuticallyacceptable salts, acids and derivatives of any of the above.

Chemotherapeutic agent also includes antibodies such as alemtuzumab(Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®,Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®,Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech),trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), andthe antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).Additional humanized monoclonal antibodies with therapeutic potential asagents in combination with the compounds of the invention include:apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine,cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab,cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab,felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin,ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab,motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab,numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab,pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab,reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab,sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan,tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab,tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab,ustekinumab, visilizumab, and the anti-interleukin-12 (ABT-874/J695,Wyeth Research and Abbott Laboratories) which is a recombinantexclusively human-sequence, full-length IgG₁ λ antibody geneticallymodified to recognize interleukin-12 p40 protein.

Chemotherapeutic agent also includes “EGFR inhibitors,” which refers tocompounds that bind to or otherwise interact directly with EGFR andprevent or reduce its signaling activity, and is alternatively referredto as an “EGFR antagonist.” Examples of such agents include antibodiesand small molecules that bind to EGFR. Examples of antibodies which bindto EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507),MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, U.S. Pat. No.4,943,533, Mendelsohn et al.) and variants thereof, such as chimerized225 (C225 or Cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see, WO96/40210, Imclone Systems Inc.); IMC-11F8, a fully human, EGFR-targetedantibody (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat.No. 5,212,290); humanized and chimeric antibodies that bind EGFR asdescribed in U.S. Pat. No. 5,891,996; and human antibodies that bindEGFR, such as ABX-EGF or Panitumumab (see WO98/50433, Abgenix/Amgen);EMD 55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996));EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR thatcompetes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); humanEGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known asE1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3 and described inU.S. Pat. No. 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanizedmAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)). Theanti-EGFR antibody may be conjugated with a cytotoxic agent, thusgenerating an immunoconjugate (see, e.g., EP659,439A2, Merck PatentGmbH). EGFR antagonists include small molecules such as compoundsdescribed in U.S. Pat. Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307,5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726,6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459,6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, aswell as the following PCT publications: WO98/14451, WO98/50038,WO99/09016, and WO99/24037. Particular small molecule EGFR antagonistsinclude OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSIPharmaceuticals); PD 183805 (CI 1033, 2-propenamide,N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-,dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®)4-(3′-Chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline,AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline,Zeneca); BIBX-1382(N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine,Boehringer Ingelheim); PKI-166((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol);(R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine);CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide);EKB-569(N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide)(Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR/HER2tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 orN-[3-chloro-4-[(3fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

Chemotherapeutic agents also include “tyrosine kinase inhibitors”including the EGFR-targeted drugs noted in the preceding paragraph;small molecule HER2 tyrosine kinase inhibitor such as TAK165 availablefrom Takeda; CP-724,714, an oral selective inhibitor of the ErbB2receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such asEKB-569 (available from Wyeth) which preferentially binds EGFR butinhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016;available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinaseinhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such ascanertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisenseagent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1signaling; non-HER targeted TK inhibitors such as imatinib mesylate(GLEEVEC®, available from Glaxo SmithKline); multi-targeted tyrosinekinase inhibitors such as sunitinib (SUTENT®, available from Pfizer);VEGF receptor tyrosine kinase inhibitors such as vatalanib(PTK787/ZK222584, available from Novartis/Schering AG); MAPKextracellular regulated kinase I inhibitor CI-1040 (available fromPharmacia); quinazolines, such as PD 153035,4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines,such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines,4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloylmethane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containingnitrothiophene moieties; PD-0183805 (Warner-Lamber); antisense molecules(e.g. those that bind to HER-encoding nucleic acid); quinoxalines (U.S.Pat. No. 5,804,396); tryphostins (U.S. Pat. No. 5,804,396); ZD6474(Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors suchas CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis/Lilly); imatinibmesylate (GLEEVEC®); PKI 166 (Novartis); GW2016 (Glaxo SmithKline);CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474(AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C11 (Imclone),rapamycin (sirolimus, RAPAMUNE®); or as described in any of thefollowing patent publications: U.S. Pat. No. 5,804,396; WO 1999/09016(American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983(Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (WarnerLambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).

Chemotherapeutic agents also include dexamethasone, interferons,colchicine, metoprine, cyclosporine, amphotericin, metronidazole,alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide,asparaginase, BCG live, bevacuzimab, bexarotene, cladribine,clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa,elotinib, filgrastim, histrelin acetate, ibritumomab, interferonalfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna,methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, plicamycin, porfimer sodium, quinacrine,rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene,tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, andpharmaceutically acceptable salts thereof.

Chemotherapeutic agents also include hydrocortisone, hydrocortisoneacetate, cortisone acetate, tixocortol pivalate, triamcinoloneacetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide,desonide, fluocinonide, fluocinolone acetonide, betamethasone,betamethasone sodium phosphate, dexamethasone, dexamethasone sodiumphosphate, fluocortolone, hydrocortisone-17-butyrate,hydrocortisone-17-valerate, aclometasone dipropionate, betamethasonevalerate, betamethasone dipropionate, prednicarbate,clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolonecaproate, fluocortolone pivalate and fluprednidene acetate; immuneselective anti-inflammatory peptides (ImSAIDs) such asphenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG)(IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such asazathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts,hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumornecrosis factor alpha (TNFα) blockers such as etanercept (Enbrel),infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia),golimumab (Simponi), Interleukin 1 (IL-1) blockers such as anakinra(Kineret), T cell costimulation blockers such as abatacept (Orencia),Interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®);Interleukin 13 (IL-13) blockers such as lebrikizumab; Interferon alpha(IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such asrhuMAb Beta7; IgE pathway blockers such as Anti-M1 prime; Secretedhomotrimeric LTa3 and membrane bound heterotrimer LTa1/β2 blockers suchas Anti-lymphotoxin alpha (LTa); radioactive isotopes (e.g., At²¹¹,I¹³¹, I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactiveisotopes of Lu); miscellaneous investigational agents such asthioplatin, PS-341, phenylbutyrate, ET-18-OCH₃, or farnesyl transferaseinhibitors (L-739749, L-744832); polyphenols such as quercetin,resveratrol, piceatannol, epigallocatechine gallate, theaflavins,flavanols, procyanidins, betulinic acid and derivatives thereof;autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol(dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinicacid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin);podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®);bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®),etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®),alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), orrisedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R);vaccines such as THERATOPE® vaccine; perifosine, COX-2 inhibitor (e.g.celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341); CCI-779;tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitor such asoblimersen sodium (GENASENSE®); pixantrone; farnesyltransferaseinhibitors such as lonafarnib (SCH 6636, SARASAR™); and pharmaceuticallyacceptable salts, acids or derivatives of any of the above; as well ascombinations of two or more of the above such as CHOP, an abbreviationfor a combined therapy of cyclophosphamide, doxorubicin, vincristine,and prednisolone; and FOLFOX, an abbreviation for a treatment regimenwith oxaliplatin (ELOXATINT™) combined with 5-FU and leucovorin.

Chemotherapeutic agents also include non-steroidal anti-inflammatorydrugs with analgesic, antipyretic and anti-inflammatory effects. NSAIDsinclude non-selective inhibitors of the enzyme cyclooxygenase. Specificexamples of NSAIDs include aspirin, propionic acid derivatives such asibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen,acetic acid derivatives such as indomethacin, sulindac, etodolac,diclofenac, enolic acid derivatives such as piroxicam, meloxicam,tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivativessuch as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamicacid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib,parecoxib, rofecoxib, rofecoxib, and valdecoxib. NSAIDs can be indicatedfor the symptomatic relief of conditions such as rheumatoid arthritis,osteoarthritis, inflammatory arthropathies, ankylosing spondylitis,psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea,metastatic bone pain, headache and migraine, postoperative pain,mild-to-moderate pain due to inflammation and tissue injury, pyrexia,ileus, and renal colic.

In certain embodiments, chemotherapeutic agents include, but are notlimited to, doxorubicin, dexamethasone, vincristine, cyclophosphamide,fluorouracil, topotecan, interferons, platinum derivatives, taxanes(e.g., paclitaxel, docetaxel), vinca alkaloids (e.g., vinblastine),anthracyclines (e.g., doxorubicin), epipodophyllotoxins (e.g.,etoposide), cisplatin, an mTOR inhibitor (e.g., a rapamycin),methotrexate, actinomycin D, dolastatin 10, colchicine, trimetrexate,metoprine, cyclosporine, daunorubicin, teniposide, amphotericin,alkylating agents (e.g., chlorambucil), 5-fluorouracil, camptothecin,cisplatin, metronidazole, and imatinib mesylate, among others. In otherembodiments, a compound disclosed herein is administered in combinationwith a biologic agent, such as bevacizumab or panitumumab.

In certain embodiments, compounds disclosed herein, or apharmaceutically acceptable composition thereof, are administered incombination with an antiproliferative or chemotherapeutic agent selectedfrom any one or more of abarelix, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenictrioxide, asparaginase, azacitidine, BCG live, bevacuzimab,fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calusterone,capecitabine, camptothecin, carboplatin, carmustine, cetuximab,chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine,dactinomycin, darbepoetin alfa, daunorubicin, denileukin, dexrazoxane,docetaxel, doxorubicin (neutral), doxorubicin hydrochloride,dromostanolone propionate, epirubicin, epoetin alfa, elotinib,estramustine, etoposide phosphate, etoposide, exemestane, filgrastim,floxuridine, fludarabine, fulvestrant, gefitinib, gemcitabine,gemtuzumab, goserelin acetate, histrelin acetate, hydroxyurea,ibritumomab, idarubicin, ifosfamide, imatinib mesylate, interferonalfa-2a, interferon alfa-2b, irinotecan, lenalidomide, letrozole,leucovorin, leuprolide acetate, levamisole, lomustine, megestrolacetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate,methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone,nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimersodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim,sorafenib, streptozocin, sunitinib maleate, talc, tamoxifen,temozolomide, teniposide, VM-26, testolactone, thioguanine, 6-TG,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine,zoledronate, or zoledronic acid.

Chemotherapeutic agents also include treatments for Alzheimer's Diseasesuch as donepezil hydrochloride and rivastigmine; treatments forParkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole,pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine;agents for treating multiple sclerosis (MS) such as beta interferon(e.g., Avonex® and Rebif®), glatiramer acetate, and mitoxantrone;treatments for asthma such as albuterol and montelukast sodium; agentsfor treating schizophrenia such as zyprexa, risperdal, seroquel, andhaloperidol; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporin,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; and agentsfor treating immunodeficiency disorders such as gamma globulin.

Additionally, chemotherapeutic agents include pharmaceuticallyacceptable salts, acids or derivatives of any of chemotherapeuticagents, described herein, as well as combinations of two or more ofthem.

Embodiments

A compound of Formula (XXI)

wherein:

X is S(O)_(p), wherein p is an integer from 0 to 2;

j is an integer from 0 to 2;

Z¹ and Z² are independently CR⁶ or N, with the proviso that at least oneof Z¹ or Z² is CR⁶ with R⁶ being a bond to L¹;

L¹ is linking group comprising at least one nitrogen atom;

E is an electrophilic moiety, wherein E is bound to L¹ via the at leastone nitrogen atom;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, alkoxy, aryl, heteroaryl, N-arylamino,N-aryl-N-alkylamino, aryloxy, and arylthio with the proviso that:

-   -   at least one R¹ is aryl, N-arylamino, N-aryl-N-alkylamino,        aryloxy, arylthio, or heteroaryl, any of which is optionally        substituted;

n is an integer from 1 to 3;

R² is selected from the group consisting of alkyl, amino, alkylamino,dialkylamino alkylamidoalkyl, arylamidoalkyl, alkylsulfonamidoalkyl,arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl aminoalkyl,alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo,haloalkyl, hydroxy, aryl, aralkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, and oxo any of which are optionallysubstituted; or two R² together with the carbon atom to which they areattached form a spirocycle or heterocycle.

m is an integer from 0 to 6; and

R⁶ is selected from the group consisting of hydrogen, alkyl, haloalkyl,cyano, halo, alkoxy, aryl, heteroaryl, trifluoromethyl and bond to L¹.

The compound wherein X is S.

The compound wherein X is S═O or SO₂.

The compound wherein j is 1.

The compound wherein m is 0.

The compound wherein m is 1.

The compound wherein Z¹ is CR⁶ with R⁶ being a bond to L¹.

The compound wherein Z² is N.

A compound of Formula (XXIIa):

wherein:

X is S(O)_(p), wherein p is an integer from 0 to 2;

j is an integer from 0 to 2;

L¹ is linking group comprising at least one nitrogen atom;

E is an electrophilic moiety, wherein E is bound to L¹ via the at leastone nitrogen atom;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

n is an integer from 0 to 2;

R² is selected from the group consisting of alkyl, alkylamino,dialkylamino alkylamidoalkyl, arylamidoalkyl, alkylsulfonamidoalkyl,arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl aminoalkyl,alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo,haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted;

m is an integer from 0 to 6; and

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted.

A compound of Formula (XXIII):

wherein:

X is S(O)_(p), wherein p is an integer from 0 to 2;

L¹ is linking group comprising at least one nitrogen atom;

E is an electrophilic moiety, wherein E is bound to L¹ via the at leastone nitrogen atom;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

n is an integer from 0 to 2; and

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted.

A compound of Formula (XXIV):

wherein:

L¹ is linking group comprising at least one nitrogen atom;

E is an electrophilic moiety, wherein E is bound to L¹ via the at leastone nitrogen atom;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

n is an integer from 0 to 2; and

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted.

210. A compound of Formula (XXV):

wherein:

L¹ is linking group comprising at least one nitrogen atom;

E is an electrophilic moiety, wherein E is bound to L¹ via the at leastone nitrogen atom;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

n is an integer from 0 to 2;

c is an integer from 0 to 4;

A is selected from the group consisting of hydroxyl, amino,N-alkylamino, N,N-dialkylamino, cycloalkylamino, N-alkylaminoalkyl,N,N-dialkylaminoalkyl, cycloalkylaminoalkyl, alkylamidoalkyl,arylamidoalkyl, alkylsulfonamidoalkyl, arylsulfonamidoalkyl, alkoxy,alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo, haloalkyl,aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted; and

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted.

217. A compound of Formula (XXVI):

wherein:

X is S(O)_(p), wherein p is an integer from 0 to 2;

j is an integer from 0 to 2;

L¹ is linking group comprising at least one nitrogen atom;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

n is an integer from 0 to 2;

R² is selected from the group consisting of alkyl, alkylamino,dialkylamino alkylamidoalkyl, arylamidoalkyl, alkylsulfonamidoalkyl,arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl aminoalkyl,alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo,haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted;

m is an integer from 0 to 6;

R⁸ is selected from the group consisting of fluorine, methyl, and—CH₂NR^(a)R^(b), wherein R^(a) and R^(b) are independently selected fromhydrogen or alkyl; or R^(a) and R^(b) combine to form a C₂-C₆ nitrogencontaining heterocycle; and

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted.

227. A compound of Formula (XXVII):

wherein:

L¹ is linking group comprising at least one nitrogen atom;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

n is an integer from 0 to 2; and

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted.

232. A compound of Formula (XXVIII):

wherein:

L¹ is linking group comprising at least one nitrogen atom;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

n is an integer from 0 to 2;

c is an integer from 0 to 4;

A is selected from the group consisting of hydroxyl, amino,N-alkylamino, N,N-dialkylamino, cycloalkylamino, N-alkylaminoalkyl,N,N-dialkylaminoalkyl, cycloalkylaminoalkyl, alkylamidoalkyl,arylamidoalkyl, alkylsulfonamidoalkyl, arylsulfonamidoalkyl, alkoxy,alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo, haloalkyl,aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted; and

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted.

237. A compound of Formula (XXIX):

wherein:

X is S(O)_(p), wherein p is an integer from 0 to 2;

j is an integer from 0 to 2;

G is selected from the group consisting of N, CH, and

wherein G¹ and G² are independently (CH₂)_(q), where q is 1 or 2;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted;

n is an integer from 0 to 2;

R² is selected from the group consisting of alkyl, alkylamino,dialkylamino alkylamidoalkyl, arylamidoalkyl, alkylsulfonamidoalkyl,arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl aminoalkyl,alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo,haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted;

m is an integer from 0 to 6;

wherein k is an integer from 0 to 4; and each R⁷ is independentlyselected from an alkyl group selected from methyl, ethyl, and propyl,any of which are optionally substituted with one or more fluorine atoms,—CH₂(CH₃)C═CF₂, cyano, propargyl, —CH₂C(O)V, wherein V is selected frommethyl, OH, NHR^(i) wherein R^(i) is hydrogen or alkyl, and cyanomethyl;or any two R⁷ may combine to form a fused-ring, spiro or bridgingbicycle, wherein any one fused-ring or bridging atom is O, S, S═O, SO₂,or NR^(j), wherein R^(j) is H, methyl or trifluoromethyl; and

wherein the acrylyl moiety linked to G is optionally substituted.

246. A compound of Formula (XXX):

wherein:

G is selected from the group consisting of N, CH, and

wherein G¹ and G² are independently (CH₂)_(q), where q is 1 or 2;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted;

n is an integer from 0 to 2;

R² is selected from the group consisting of alkyl, alkylamino,dialkylamino alkylamidoalkyl, arylamidoalkyl, alkylsulfonamidoalkyl,arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl aminoalkyl,alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo,haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted;

m is an integer from 0 to 4;

wherein k is an integer from 0 to 4; and each R⁷ is independentlyselected from an alkyl group selected from methyl, ethyl, and propyl,any of which are optionally substituted with one or more fluorine atoms,—CH₂(CH₃)C═CF₂, cyano, propargyl, —CH₂C(O)V, wherein V is selected frommethyl, OH, NHR^(i) wherein R^(i) is hydrogen or alkyl, and cyanomethyl;or any two R⁷ may combine to form a fused-ring, spiro or bridgingbicycle, wherein any one fused-ring or bridging atom is O, S, S═O, SO₂,or NR^(j), wherein R^(j) is H, methyl or trifluoromethyl; and

wherein the acrylyl moiety linked to G is optionally substituted.

252. A compound of Formula (XXXI):

wherein:

G is selected from the group consisting of N, CH, and

wherein G¹ and G² are independently (CH₂)_(q), where q is 1 or 2;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

n is an integer from 0 to 2;

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted;

c is an integer from 0 to 4;

A is selected from the group consisting of hydroxyl, amino,N-alkylamino, N,N-dialkylamino, cycloalkylamino, N-alkylaminoalkyl,N,N-dialkylaminoalkyl, cycloalkylaminoalkyl, alkylamidoalkyl,arylamidoalkyl, alkylsulfonamidoalkyl, arylsulfonamidoalkyl, alkoxy,alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo, haloalkyl,aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted;

wherein k is an integer from 0 to 4; and each R⁷ is independentlyselected from an alkyl group selected from methyl, ethyl, and propyl,any of which are optionally substituted with one or more fluorine atoms,—CH₂(CH₃)C═CF₂, cyano, propargyl, —CH₂C(O)V, wherein V is selected frommethyl, OH, NHR^(i) wherein R^(i) is hydrogen or alkyl, and cyanomethyl;or any two R⁷ may combine to form a fused-ring, spiro or bridgingbicycle, wherein any one fused-ring or bridging atom is O, S, S═O, SO₂,or NR^(j), wherein R^(j) is H, methyl or trifluoromethyl; and

wherein the acrylyl moiety linked to G is optionally substituted.

264. A compound of Formula (XXXIV):

wherein:

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

n is an integer from 0 to 2;

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted;

c is an integer from 0 to 4;

A is selected from the group consisting of hydroxyl, amino,N-alkylamino, N,N-dialkylamino, cycloalkylamino, N-alkylaminoalkyl,N,N-dialkylaminoalkyl, cycloalkylaminoalkyl, alkylamidoalkyl,arylamidoalkyl, alkylsulfonamidoalkyl, arylsulfonamidoalkyl, alkoxy,alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo, haloalkyl,aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted;

wherein k is an integer from 0 to 4; and each R⁷ is independentlyselected from an alkyl group selected from methyl, ethyl, and propyl,any of which are optionally substituted with one or more fluorine atoms,—CH₂(CH₃)C═CF₂, cyano, propargyl, —CH₂C(O)V, wherein V is selected frommethyl, OH, NHR^(i) wherein R^(i) is hydrogen or alkyl, and cyanomethyl;or any two R⁷ may combine to form a fused-ring, spiro or bridgingbicycle, wherein any one fused-ring or bridging atom is O, S, S═O, SO₂,or NR^(j), wherein R^(j) is H, methyl or trifluoromethyl; and

wherein the acrylyl moiety linked to N is optionally substituted.

268. A compound of Formula (XXXV):

wherein:

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

n is an integer from 0 to 2;

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted;

c is an integer from 0 to 4;

A is selected from the group consisting of hydroxyl, amino,N-alkylamino, N,N-dialkylamino, cycloalkylamino, N-alkylaminoalkyl,N,N-dialkylaminoalkyl, cycloalkylaminoalkyl, alkylamidoalkyl,arylamidoalkyl, alkylsulfonamidoalkyl, arylsulfonamidoalkyl, alkoxy,alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo, haloalkyl,aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted;

R^(7A), R^(7B), R^(7C), and R^(7D) are independently selected fromhydrogen, alkyl, and cyanoalkyl; or any two R^(7A-D) may combine to forma fused-ring or bridging bicycle, wherein any one fused-ring or bridgingatom is O, S, S═O, or SO₂. and

wherein the acrylyl moiety linked to N is optionally substituted.

282. A compound of Formula (XXXVI):

wherein:

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

n is an integer from 0 to 2;

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted;

R^(7A), R^(7B), R^(7C), and R^(7D) are independently selected fromhydrogen, alkyl, and cyanoalkyl; or any two R^(7A-D) may combine to forma fused-ring or bridging bicycle, wherein any one fused-ring or bridgingatom is O, S, S═O, or SO₂; and

wherein the acrylyl moiety linked to N is optionally substituted.

283. The compound wherein Ar creates axial asymmetry.

284. The compound wherein the compound is a single rotamer.

285. The compound wherein Ar is:

wherein R⁹, R¹⁰, R¹¹, R¹², and R¹³ are each independently selected fromthe group consisting of hydrogen, halo, alkyl, alkoxy, haloalkyl,trifluoromethyl, cycloalkyl and any two adjacent R⁹, R¹⁰, R¹¹, R¹², andR¹³ together combine to form a further fused ring that is an aromaticring optionally comprising 1 to 3 heteroatoms independently selectedfrom N, O or S, the further fused ring being optionally substituted.

286. The compound wherein R^(7B) is methyl.

287. The compound wherein a stereogenic center created by the R^(7B)methyl group is in the R-configuration.

288. The compound wherein a stereogenic center created by the R^(7B)methyl group is in the S-configuration.

289. The compound wherein R^(7C) is methyl.

290. The compound wherein a stereogenic center created by the R^(7C)methyl group is in the R-configuration.

291. The compound wherein a stereogenic center created by the R^(7C)methyl group is in the S-configuration.

292. The compound wherein R^(7D) is hydrogen.

293. The compound wherein R^(7A) is cyanomethyl.

294. The compound wherein a stereogenic center created by thecyanomethyl group is in the R-configuration.

295. The compound wherein a stereogenic center created by thecyanomethyl group is in the S-configuration.

296. A compound of Formula (XXXVII):

wherein:

E is an electrophilic moiety;

G is selected from the group consisting of N, CH, and

wherein G¹ and G² are independently (CH₂)_(q), where q is 1 or 2;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

n is an integer from 0 to 2;

R^(7A), R^(7B), R^(7C), and R^(7D) are independently selected fromhydrogen, alkyl, and cyanoalkyl; or any two R^(7A-D) may combine to forma fused-ring or bridging bicycle, wherein any one fused-ring or bridgingatom is O, S, S═O, or SO₂.

wherein R⁹, R¹⁰, R¹¹, R¹², and R¹³ are each independently selected fromthe group consisting of hydrogen, halo, alkyl, alkoxy, haloalkyl,trifluoromethyl, cycloalkyl and any two adjacent R⁹, R¹⁰, R¹¹, R¹², andR¹³ together combine to form a further fused ring that is an aromaticring optionally comprising 1 to 3 heteroatoms independently selectedfrom N, O or S, the further fused ring being optionally substituted;

wherein R¹⁴ and R¹⁵ are selected from the group consisting of hydrogen,hydroxyl, amino, N-alkylamino, dialkylamino, N-alkylamino alkyl,N,N-dialkylamino, N,N-dialkylamino alkyl, cycloalkylamino,cycloalkylaminoalkyl, alkylamidoalkyl, arylamidoalkyl,alkylsulfonamidoalkyl, arylsulfonamidoalkyl, alkoxy, alkoxyalkyl,cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo, haloalkyl, aryl,aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted, with theproviso that one of R¹⁴ or R¹⁵ is hydrogen; and

wherein E is optionally substituted.

309. The compound wherein the compound is a single rotamer of Formula(XXXVIIa):

310. The compound wherein the compound is a single rotamer of Formula(XXXVIIb):

311. A compound of Formula (XXXVIII):

wherein:

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

n is an integer from 0 to 2;

R^(7A), R^(7B), R^(7C), and R^(7D) are independently selected fromhydrogen, alkyl, and cyanoalkyl; or any two R^(7A-D) may combine to forma fused-ring or bridging bicycle, wherein any one fused-ring or bridgingatom is O, S, S═O, or SO₂.

wherein R⁹, R¹⁰, R¹¹, R¹², and R¹³ are each independently selected fromthe group consisting of hydrogen, halo, alkyl, alkoxy, haloalkyl,trifluoromethyl, cycloalkyl and any two adjacent R⁹, R¹⁰, R¹¹, R¹², andR¹³ together combine to form a further fused ring that is an aromaticring optionally comprising 1 to 3 heteroatoms independently selectedfrom N, O or S, the further fused ring being optionally substituted.

wherein the acrylyl moiety linked to N is optionally substituted.

324. A compound of Formula (XXXIX):

wherein * is a stereogenic center;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

n is an integer from 0 to 2;

R^(7A), R^(7B), R^(7C), and R^(7D) are independently selected fromhydrogen, alkyl, and cyanoalkyl; or any two R^(7A-D) may combine to forma fused-ring or bridging bicycle, wherein any one fused-ring or bridgingatom is O, S, S═O, or SO₂.

wherein R⁹, R¹⁰, R¹¹, R¹², and R¹³ are each independently selected fromthe group consisiting of hydrogen, halo, alkyl, alkoxy, haloalkyl,trifluoromethyl, cycloalkyl and any two adjacent R⁹, R¹⁰, R¹¹, R¹², andR¹³ together combine to form a further fused ring that is an aromaticring optionally comprising 1 to 3 heteroatoms independently selectedfrom N, O or S, the further fused ring being optionally substituted.

c is an integer from 0 to 4;

A is selected from the group consisting of hydroxyl, amino,N-alkylamino, N,N-dialkylamino, cycloalkylamino, N-alkylaminoalkyl,N,N-dialkylaminoalkyl, cycloalkylaminoalkyl, alkylamidoalkyl,arylamidoalkyl, alkylsulfonamidoalkyl, arylsulfonamidoalkyl, alkoxy,alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo, haloalkyl,aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted; and

wherein the acrylyl moiety linked to N is optionally substituted.

337. A compound of Formula (XL):

wherein:

X is S(O)_(p), wherein p is an integer from 0 to 2;

j is an integer from 0 to 2;

L¹ is linking group comprising at least one nitrogen atom;

each R¹ is is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

n is an integer from 0 to 2;

R² is selected from the group consisting of alkyl, alkylamino,dialkylamino alkylamidoalkyl, arylamidoalkyl, alkylsulfonamidoalkyl,arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl aminoalkyl,alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halo,haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, any of which are optionally substituted;

m is an integer from 0 to 6;

R⁶ is is selected from the group consisting of hydrogen, alkyl,haloalkyl, cyano, halo, alkoxy, aryl, heteroaryl, and trifluoromethyl;

R⁸ is selected from the group consisting of fluorine, methyl, and—CH₂NR^(a)R^(b), wherein R^(a) and R^(b) are independently selected fromhydrogen or alkyl; or R^(a) and R^(b) combine to form a C₂-C₆ nitrogencontaining heterocycle; and

Ar is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio,heteroaryl, N-heteroarylamino, N-heteroaryl-N-alkylamino, heteroaryloxy,or heteroarylthio, any of which is optionally substituted.

347. The compound given by Formula XLI:

wherein:

Y is selected from the group consisting of hydrogen; N-linkedheteroaromatic ring; N-linked azetidinyl optionally substituted withfluorine, CO—NR′R″, or spiro-linked oxetane; OR^(a); and Z³R^(b)R^(c);

R′ and R″ are independently hydrogen, alkyl or cycloalkyl;

Z³ is CH, COH, or N;

m is an integer from 1 to 5;

R^(a) is hydrogen, methyl, ethyl trifluoromethyl, heterocyclyl, orheterocyclylalkyl;

R^(b) and R^(c) are independently selected from alkyl, alkyl having oneor more fluorine substitutions, cycloalkyl, oxetanyl, and N-methylprolinyl; or R^(b) and R^(c) combine to form a cyclic structure A1:

wherein q is an integer from 1 to 4; M is selected from a bond, O, S,SO, SO₂, CH₂, NH, NMe, N-ethyl, N-oxetanyl, and N-cyclopropyl, whereineach C—H of each alkylene, alkyl or cycloalkyl group is independentlyoptionally substituted with a fluorine atom;

each R^(s) is independently fluorine, oxo, alkoxy, or CO—NR′R″, or anytwo R^(s) combine to form a 1 to 3 carbon atom bridge, wherein the 1 to3 carbon atom bridge is optionally substituted with one or more fluorineatoms;

each R′ and R″ is independently hydrogen, alkyl or cycloalkyl;

j is an integer from 0 to 2;

Z¹ and Z² are independently CR⁶ or N, with the proviso that at least oneof Z¹ or Z² is CR⁶ with R⁶ being a bond to L¹;

L¹ is linking group comprising at least one nitrogen atom;

E is an electrophilic moiety, wherein E is bound to L¹ via the at leastone nitrogen atom;

each R¹ is independently selected from the group consisting of acyl,alkyl, carboxamide, cyano, cycloalkyl, halo, haloalkyl, trifluoromethyl,alkoxy, aryl, heteroaryl, N-arylamino, N-aryl-N-alkylamino, aryloxy,cycloalkyl, heterocyclyl, and arylthio with the proviso that at leastone R¹ is aryl, N-arylamino, N-aryl-N-alkylamino, aryloxy, arylthio, orheteroaryl, any of which is optionally substituted;

n is an integer from 1 to 3;

m is an integer from 0 to 6;

R³, R⁴, and R⁵ are each independently selected from the group consistingof hydrogen alkyl, halo, alkoxy, aryl, heteroaryl, and cycloalkyl, anyof which are optionally substituted; and

R⁶ is selected from the group consisting of hydrogen, alkyl, haloalkyl,cyano, halo, alkoxy, aryl, heteroaryl, trifluoromethyl and bond to L¹,and pharmaceutically acceptable salts thereof.

348. The compound having the formula XLII

wherein:

X is S(O)_(p), wherein p is an integer from 0 to 2;

j is an integer from 0 to 2;

B is bridging group comprising 1 to 3 carbon atoms, wherein any onecarbon atom is optionally replaced by O, S, SO₂, or N-alkyl;

E is an electrophilic moiety;

each R¹ is independently selected from the group consisting of acyl,alkyl, carboxamide, cyano, cycloalkyl, halo, haloalkyl, trifluoromethyl,alkoxy, aryl, heteroaryl, N-arylamino, N-aryl-N-alkylamino, aryloxy,cycloalkyl, heterocyclyl, and arylthio with the proviso that:

-   -   at least one R¹ is aryl, N-arylamino, N-aryl-N-alkylamino,        aryloxy, arylthio, or heteroaryl, any of which is optionally        substituted;

n is an integer from 1 to 3;

R² is selected from the group consisting of alkyl, alkylamino,dialkylamino, alkylamidoalkyl, arylamidoalkyl, alkylsulfonamidoalkyl,arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl aminoalkyl, amido,amido alkyl, alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl,hydroxyalkyl, halo, haloalkyl, aryl, aralkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, any of which areoptionally substituted;

m is an integer from 0 to 6;

R³, R⁴, and R⁵ are each independently selected from the group consistingof hydrogen alkyl, halo, alkoxy, aryl, heteroaryl, and cycloalkyl, anyof which are optionally substituted, and pharmaceutically acceptablesalts thereof.

349. A compound selected from Tables 1-7.

353. A compound of Formula (XLIII) or pharmaceutically acceptable saltthereof:

wherein:

X is O or S;

L¹ is linking group comprising at least one nitrogen atom;

E is an electrophilic moiety, wherein E is bound to L¹ via the at leastone nitrogen atom;

each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cycloalkyl, halo, haloalkyl,trifluoromethyl, and alkoxy;

-   -   Ar is selected from the group consisting of aryl, N-arylamino,        N-aryl-N-alkylamino, aryloxy, arylthio, or heteroaryl, any of        which is optionally substituted;

n is an integer from 1 to 2;

each R² is independently selected from the group consisting optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, —CHR′R″, —OR′, —SR′, and —NR′, R″; whereineach R′ or R″ is selected from the group consisting of hydrogen, alkyl,alkoxy, alkoxyalkyl, hydroxy, cycloalkoxy, _(cyano), cyanoalkyl, amido,amidoalkyl, N-alkylamido, N-alkylamidoalkyl, N,N-dialkylamido,N,N-dialkylamidoalkyl, amino, aminoalkyl, N-alkyl amino, N-alkylaminoalkyl, N,N-dialkylamino, and N,N-dialkylaminoalkyl, any of whichare optionally substituted; or any two R′ and R″ combine to form3-7-membered ring, optionally comprising 1 or 2 heteroatoms selectedfrom N, O, or S; or any two R² combine to form a spirocycle comprising 0to 2 heteroatoms selected from N, O, or S; and

m is an integer from 0 to 6.

360. A compound of Formula (XLIV) or pharmaceutically acceptable saltthereof:

wherein:L¹ is linking group comprising at least one nitrogen atom;each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cyclopropyl, halo, haloalkyl,trifluoromethyl, alkoxy,n is 1 or 2;each R² is independently selected from the group consisting optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, —CHR′R″, —OR′, —SR′, and —NR′, R″; whereineach R′ or R″ is selected from the group consisting of hydrogen, alkyl,alkoxy, alkoxyalkyl, hydroxy, cycloalkoxy, cyano, cyanoalkyl, amido,amidoalkyl, N-alkylamido, N-alkylamidoalkyl, N,N-dialkylamido,N,N-dialkylamidoalkyl, amino, aminoalkyl, N-alkyl amino, N-alkylaminoalkyl, N,N-dialkylamino, and N,N-dialkylaminoalkyl, any of whichare optionally substituted; or any two R′ and R″ combine to form3-7-membered ring, optionally comprising 1 or 2 heteroatoms selectedfrom N, O, or S; or any two R² combine to form a spirocycle comprising 0to 2 heteroatoms selected from N, O, or S;m is 1 or 2; andAr is a phenyl group optionally substituted with one or more alkyl,cycloalkyl, fluoro, chloro, bromo, iodo, trifluoromethyl or cyano.

365. A compound of Formula (XLV) or pharmaceutically acceptable saltthereof:

wherein:L¹ is linking group comprising at least one nitrogen atom;each R¹ is an optional substitution independently selected from thegroup consisting of alkyl, cyano, cyclopropyl, halo, haloalkyl,trifluoromethyl, alkoxy,n is 1 or 2;R^(2a) and R^(2b) are independently selected from the group consistingof hydrogen, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, —CHR′R″, —OR′, —SR′,and —NR′, R″; wherein each R′ or R″ is selected from the groupconsisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, hydroxy,cycloalkoxy, _(cyano), cyanoalkyl, amido, amidoalkyl, N-alkylamido,N-alkylamidoalkyl, N,N-dialkylamido, N,N-dialkylamidoalkyl, amino,aminoalkyl, N-alkyl amino, N-alkyl aminoalkyl, N,N-dialkylamino,N,N-dialkylaminoalkyl, any of which are optionally substituted; or R′and R″ combine to form 3-7-membered ring, optionally comprising 1 or 2heteroatoms selected from N, O, or S, or R^(2a) and R^(2b) combine toform a spirocycle comprising 0 to 2 heteroatoms selected from N, O, orS; andAr is a phenyl optionally substituted with one or more alkyl,cycloalkyl, fluoro, chloro, bromo, iodo, trifluoromethyl or cyano.

366. The compound wherein L¹ is

wherein k is an integer from 0 to 4; and each R⁷ is independentlyselected from methyl, and cyanomethyl, or any two R⁷ combine to form abridge or spirocycle structure optionally comprising a heteroatom in thebridge or spirocycle selected from S, SO₂, O or N, and wherein thebridge or spirocycle structure is optionally substituted with oxo.

367. The compound of any of the preceding embodiments wherein n is 1 andR¹ is ortho to Ar.

368. The compound of any of the preceding embodiments wherein R¹ ischloro or trifluoromethyl.

369. The compound of any of the preceding embodiments wherein Ar is aphenyl ring comprising 1 to 3 fluorine substitutions.

370. The compound of any of the preceding embodiments wherein R^(2a) ishydrogen and R^(2b) is not hydrogen.

371. The compound of any of the preceding embodiments wherein R^(2a) ishydrogen and R^(2b) is not hydrogen.

372. The compound of any of the preceding embodiments wherein R^(2a) andR^(2b) combine to form a spirocyclic carbocycle or heterocycle.

373. The compound having the structure of formula XLVa or XLVb:

374. The compound having the structure of formula XLVc or XLVd:

375. The compound having the structure of formula XLVe or XLVf:

376. The compound having the structure of formula XLVg or XLVh:

377. A compounds selected from:

378. A pharmaceutical composition comprising a compound of embodiments353 to 377.

379. A method of treating a subject with a cancer comprising a K-RasG12C mutation comprising administering to the subject a compound of anyone of embodiments 353 to 377 or pharmaceutical composition thereof.

380. Use of a compound of any one of embodiments 353 to 377 in themanufacture of a medicament for the treatment of a cancer comprising aK-Ras G12C mutation.

381. A pharmaceutically acceptable salt of any one of the compounds ofembodiments 1 to 377.

IX. Examples

The following Examples are provided to illustrate exemplary embodimentsof the compounds disclosed herein and their preparation.

Various starting materials and other reagents were purchased fromcommercial suppliers, such as Aldrich Chemical Company, and used withoutfurther purification, unless indicated otherwise. Compounds are preparedaccording to the exemplary procedures provided herein and modificationsthereof known to those of skill in the art. The following abbreviationsare used throughout the Examples: “Ac” means acetyl, “AcO” or “OAc”means acetoxy, “ACN” means acetonitrile, “aq” means aqueous, “atm” meansatmosphere(s), “BOC”, “Boc” or “boc” means N-tert-butoxycarbonyl, “Bn”means benzyl, “Bu” means butyl, “nBu” means normal-butyl, “tBu” meanstert-butyl, “Cbz” means benzyloxycarbonyl, “DBU” means1,8-diazabicyclo[5.4.0]undec-7-ene, “DCM” (CH₂Cl₂) means methylenechloride/dichloromethane, “de” means diastereomeric excess, “DEA” meansdiethylamine, “DIPEA” means diisopropylethyl amine, “DMA” meansN,N-dimethylacetamide, “DMAP” means 4-dimethylaminopyridine, “DMF” meansN,N-dimethyl formamide, “DMSO” means dimethylsulfoxide, “DPPP” means1,3-bis(diphenylphosphino)propane, “ee” means enantiomeric excess, “Et”means ethyl, “EtOAc” means ethyl acetate, “EtOH” means ethanol, “HATU”means 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, “HOAc” or “AcOH” means acetic acid, “i-Pr”means isopropyl, “IPA” means isopropyl alcohol, “LDA” means lithiumdiisopropylamide, “LiHMDS” or “LHMDS” means lithiumhexamethyldisilazide, “Me” means methyl, “MeOH” means methanol, “MgSO₄”means magnesium sulphate, “MS” means mass spectrometry, “MTBE” meansmethyl tert-butyl ether, Na₂SO₄” means sodium sulphate, “NMP” means1-methyl 2-pyrrolidinone, “Ph” means phenyl, “sat.” means saturated,“SFC” means supercritical fluid chromatography, “TBME” or “MTBE” meanstert-butyl methyl ether, “TEA” means triethyl amine, “TFA” meanstrifluoroacetic acid, “THF” means tetrahydrofuran, “TLC” means thinlayer chromatography, “Rf” means retention fraction, “about” meansapproximately, “rt” means retention time, “RT” means room temperature,“h” means hours, “min” means minutes, “N” means Normal, “M” means molar,“mL” means milliliter, “mmol” means millimoles, “μmol” means micromoles,“eq.” means equivalent, “° C.” means degrees Celsius, and “Pa” meanspascals. ¹H-NMR spectra are reported in ppm, and were obtained as CDCl₃solutions (7.25 ppm), DMSO-D₆ solutions (2.50 ppm), or CD₃OD solutions(3.4 ppm and 4.8 ppm), any may have used internal tetramethylsilane(0.00 ppm) as an internal standard when appropriate. Other NMR solventswere used as needed. When peak multiplicities are reported, thefollowing abbreviations are used: s (singlet), d (doublet), t (triplet),m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet oftriplets). Coupling constants, when given, are reported in Hertz (Hz).

Example Pyrimidone-Thiomorpholines-A

1. General Information:

2. Preparation of Compound 2

To a solution of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (2.68 g,10 mmol, 1.0 eq.) in DMF (27 mL) was added DIPEA (6.45 g, 50 mmol, 10eq.), NH₄Cl (3.20 g, 60 mmol, 6 eq.) and HATU (7.6 g, 20 mmol, 2 eq.)under N₂ atmosphere at RT. Then the reaction mixture was stirred for 2hours, diluted with MTBE (100 mL), washed with 0.5N HCl aq. (50 mL),brine (50 mL) and dried over Na₂SO₄. The organic layer was concentratedin vacuo. The residue obtained was purified by a chromatography (0-50%EtOAc/petroleum ether) to provide the product 2 as a yellow solid (2.3g, yield: 86%). LC-MS: [M+H]⁺=267

3. Preparation of Compound 3

To a solution of 2-amino-4-bromo-5-chloro-3-fluorobenzamide (2.67 g, 10mmol, 1.0 eq.) in CF₃COOH (27 mL) was added hydrogen peroxide (5.7 g, 50 mmol, 5 eq.). The reaction was stirred at 50° C. for 0.5 hour. Thendiluted with MTBE (150 mL), washed with water (100 mL), brine (100 mL),and then dried over Na₂SO₄. The organic layer was concentrated in vacuo,the residue obtained was purified by a chromatography (0-100%EtOAc/petroleum ether) to provide the product 3 as a yellow solid (1.8g, yield: 60%). LC-MS: [M+H]⁺=297

4. Preparation of Compound 5

To a solution of 4-bromo-5-chloro-3-fluoro-2-nitrobenzamide (3.0 g, 10mmol, 1.0 eq) in EtOH (30 ml) and water (6 mL) was added2-((tert-butyldiphenylsilyl)oxy)ethane-1-thiol (3.2 g, 10 mmol, 1.0 eq),potassium carbonate (4.2 g, 30 mmol, 3.0 eq). Then the reaction mixturewas stirred at 50° C. for 2 hours. The solvent was removed to afford 6.5g of the crude product which was used in the subsequent step withoutfurther purification. LC-MS: [M+H]⁺=593

5. Preparation of Compound 6

To a solution of compound 5 (6.5 g crude, 10 mmol, 1.0 eq.) in CH₃COOH(120 mL) was added Iron powder (2.8 g, 50 mmol, 5 eq.). The reactionmixture was stirred at 50° C. for 2 h. After filtration, the collectedsolid was washed with EtOAc (500 mL). The organic phase was washed withwater 300 mL, brine 300 mL and concentrated in vacuo. The residueobtained was purified by a chromatography (0-100% EtOAc/petroleum ether)to provide the product 6 as a yellow solid (2.8 g, yield: 50%). LC-MS:[M+H]⁺=563

6. Preparation of Compound 7

To a solution of compound 6 (5.6 g, 10 mmol, 1.0 eq.) in DCM (110 mL)was added DIPEA (2.6 g, 20 mmol, 2 eq.), CDI (4.9 g, 30 mmol, 3.0 eq.)at rt. The reaction mixture was stirred for 16 hours. After filtration,the filter cake was washed with petroleum ether (50 mL) and dried toafford the product 7 as an off-white solid (4.7 g, yield: 80%). LC-MS:[M+H]⁺=589

7. Preparation of Compound 8

To a solution of compound 7 (5.9 g, 10 mmol, 1.0 eq.) in THF (60 mL) wasadded tetrabutylammonium fluoride (10 mL, 10 mmol, 1.0 eq.). Thereaction mixture was stirred for 3 hours. After diluted with EtOAc (150mL), washed with H₂O (50 mL) and brine (50 mL). The organic layer wasdried over Na₂SO₄ and concentrated in vacuo to give the crude product 8as an off-white solid (3.16 g, yield: 90%).

8. Preparation of Compound 9

To a solution of7-bromo-6-chloro-8-((2-hydroxyethyl)thio)quinazoline-2,4-diol (3.5 g, 10mmol, 1.0 eq.) in THF (100 mL) was added PPh₃ (4.5 g, 17 mmol, 1.7 eq.),then DEAD (3.0 g, 17 mmol, 1.7 eq.) at −10˜0° C. The reaction mixturewas stirred for 1 hour. After diluted with EtOAc (100 mL), washed withwater (100 mL), brine (100 mL). The organic layer was dried over Na₂SO₄and concentrated in vacuo. The residue obtained was diluted with DCM(100 mL) and stirred for 2 hours. After filtration, the filter cake waswashed with DCM (50 mL) and dried to give the product 9 as an off-whitesolid (1.5 g, yield: 45%). LC-MS: [M+H]⁺=333

9. Preparation of Compound 2

To a solution of Compound 1 (1.2 mmol, 400 mg) was in toluene was addedPOCl₃ (3 mL), DIPEA (2.4 mmol, 309 mg) subsequently. The mixture wasstirred at 120° C. for 1.5 hrs. The solvent was removed in vacuo. Thecrude product was used the next step without further purification.

To the solution of above crude product in DCM (10 mL) was added DIPEA(2.4 mmol, 309 mg), followed by addition of tert-butyl(S)-3-methylpiperazine-1-carboxylate (1.2 mmol, 187 mg). Then thereaction solution was stirred at rt for 1 hr. The mixture was dilutedwith DCM and washed with water. The organic phase was dried over Na₂SO₄.After filtration, the solvent was removed in vacuo. The residue waspurified by a chromatography with (30-50% EtOAc/petroleum ether) toprovide compound 2 as a yellow solid (400 mg, 65%). LC-MS:[M+H]⁺=515.0/517.0, RT=1.735 min. ¹H NMR (400 MHz, CDCl₃) δ 7.44 (s,1H), 4.64 (s, 1H), 4.40 (s, 2H), 4.07 (s, 1H), 3.89 (s, 1H), 3.52 (s,1H), 3.26-3.19 (m, 3H), 3.11 (s, 2H), 1.49 (s, 9H), 1.40 (d, J=6.7 Hz,3H).

10. Preparation of Compound 3

To a solution of Compound 2 (0.28 mmol, 150 mg) in dioxane (5 mL) wasadded (5-chloro-2-fluorophenyl)boronic acid (0.37 mmol, 63 mg),Pd(dppf)Cl₂ (0.056 mmol, 41 mg), and CsF (0.56 mmol, 85 mg) in N₂atmosphere successively. After the reaction was finished, the mixturewas filtered, diluted with EtOAc and washed with water. The organicphase was dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by a chromatography with (30-50% EtOAc/petroleum ether) toafford compound 3 as light-yellow solid (110 mg, 67%). LC-MS: [M+H]⁺=NOSignal, RT=1.836 min.

11. Preparation of Compound 5

Compound 3 (0.19 mmol, 110 mg) was dissolved in TFA (2 mL), and themixture was stirred at rt overnight. After the reaction was finished,the mixture was washed with saturated aqueous sodium carbonate, dilutedwith brine and extracted with DCM. The organic phase was dried overNa₂SO₄. The solvent was removed in vacuo to give the crude product whichwas used to the next step without further purification.

To a solution of above product was in DCM (5 mL) was added DIPEA (1.0mmol, 127 mg), followed by acryloyl chloride (0.24 mmol, 22 mg) at 0° C.Then the mixture was stirred for 1 h. The reaction mixture was washedwith saturated aqueous sodium carbonate, brine and extracted with DCM.The organic phase was dried over Na₂SO₄, and the solvent was removed invacuo. The residue was purified by pre-HPLC to give compound 5 (yield:40%). LCMS: [M+H]+=521.0, RT=1.566 min. ¹H NMR (401 MHz, DMSO) δ 7.64(d, J=10.8 Hz, 2H), 7.55-7.41 (m, 2H), 6.83 (d, J=10.2 Hz, 1H),6.30-6.06 (m, 1H), 5.74 (dd, J=10.4, 2.0 Hz, 1H), 4.65 (d, J=31.4 Hz,1H), 4.47-4.18 (m, 2H), 4.03 (dd, J=27.6, 13.3 Hz, 3H), 3.68-3.41 (m,2H), 3.27-3.07 (m, 2H), 3.06-2.87 (m, 1H), 1.26 (dd, J=12.9, 6.2 Hz,3H).

The different-alkyl intermediates were synthesized using correspondingboronic acid for Suzuki reaction and acid (acid chloride or anhydride)for amid formation. The otherfsteps were conducted using the conditionsdescribed above.

TABLE 2a Summary of Examples % CAF 10 uM @ Ex.# Name Structure ¹H NMR MS60 min 62a 7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(5-cyclopropyl-2- fluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, MeOH- d4) δ 7.66 (dd, J = 9.0 Hz, 1H), 7.26-7.18 (m,1H), 7.11 (t, J = 9.1 Hz, 1H), 6.97-6.90 (m, 1H), 6.89-6.72 (m, 1H),6.29 (dd, J = 16.8, 8.2 Hz, 1H), 5.81 (dd, J = 10.6, 1.9 Hz, 1H),4.83-4.70 (m, 1H), 4.60-3.96 (m, 5H), 3.77-3.41 (m, 2H), 3.26-3.03 (m,3H), 2.00-1.91 (m, 1H), 1.40 (dd, J = 21.1, 6.8 Hz, 3H), 1.03-0.95 (m,2H), 0.72-0.64 (m, 2H): 525.04 67 63 (S,E)-9-chloro-10-(3- chloro-5-fluorophenyl)-7-(4- (4,4-difluorobut-2- enoyl)-2- methylpiperazin-1-yl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (400 MHz, CDCl₃) δ 7.47 (d, J = 6.8 Hz, 1H), 7.23- 7.20 (m, 1H),7.05-7.04 (m, 1H), 6.90-6.88 (m, 1H), 6.83- 6.74 (m, 2H), 6.29 (t, J =54.8 Hz, 1H), 4.87-4.14 (m, 5H), 3.93-3.52 (m, 3H), 3.13-3.01 (m, 3H),1.45-1.40 (m, 3H). 569.43 75 64 (S)-9-chloro-10-(3- chloro-5-fluorophenyl)-7-(4- (2-fluoroacryloyl)-2- methylpiperazin-1-yl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (400 MHz, CDCl₃) δ 7.47 (s, 1H), 7.23-7.20 (m, 1H), 7.05-7.04 (m,1H), 6.90- 6.88 (m, 1H), 5.37 (dd, J = 47.2 Hz, 3.2 Hz, 1H), 5.20 (dd, J= 16.8 Hz, 3.6 Hz, 1H), 4.78-4.74 (m, 1H), 4.50-3.80 (m, 5H), 3.64-3.56(m, 2H), 3.09 (t, J = 4.8 Hz, 3H), , 1.44 (d, J = 6.8 Hz, 3H). 537.41 365 (S)-9-chloro-10-(3- chloro-5- fluorophenyl)-7-(4-(2-fluoroacryloyl)-2- methylpiperazin-1- yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (400 MHz, CDCl₃) δ 7.47-7.45 (d, J = 7.2 H, 1H), 7.23-7.20 (m,1H), 7.05-7.04 (m, 1H), 6.99-6.95 (m, 1H), 6.90-6.88 (m, 1H), 4.87-3.91(m, 5H), 3.75-3.53 (m, 2H), 3.17-2.99 (m, 3H), 1.45-1.40 (dd, J = 10.8Hz, 6.4 Hz, 3H). 587.42 70 66 (S)-7-(4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(3,5- difluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (400 MHz, CDCl₃) δ 7.47 (s, 1H), 6.95-6.90 (m, 1H), 6.80-6.78 (m,2H), 6.63- 6.52 (m, 1H), 6.39-6.35 (m, 1H), 5.80-5.77 (d, J = 10.4 Hz,1H), 4.88-4.85 (m, 0.5H), 4.70-4.62 (m, 1H), 4.43-4.28 (m, 3H),4.16-3.96 (m, 1H), 3.84-3.80 (m, 0.5H), 3.66-3.47 (m, 2H), 3.12-2.94 (m,3H), 1.49-1.41 (m, 3H). 502.96 91 67 (S,E)-9-chloro-7-(4-(4,4-difluorobut-2- enoyl)-2- methylpiperazin-1- yl)-10-(3,5-difluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

1H NMR (400 MHz, CDCl₃) δ 7.46 (d, J = 6.8 Hz, 1H), 6.95- 6.91 (m, 1H),6.86-6.70 (m, 4H), 6.29 (t, J = 56 Hz, 1H), 4.87-4.86 (m, 0.5H),4.68-4.65 (m, 1H), 4.47-4.32 (m, 3H), 4.17-3.92 (dd, J = 13.6 Hz, 1H),3.77-3.74 (m, 0.5H), 3.66-3.51 (m, 2H), 3.16-3.00 (m, 3H), 1.45-1.40 (m,3H). 552.97 87 71 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10- (isoquinolin-8-yl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, MeOD) δ 8.84-8.14 (m, 2H), 8.00 (d, J = 8.3 Hz, 1H),7.92-7.74 (m, 2H), 7.67 (d, J = 9.6 Hz, 1H), 7.46 (dt, J = 7.1, 1.4 Hz,1H), 6.85-6.62 (m, 1H), 6.19 (ddd, J = 17.0, 7.3, 2.0 Hz, 1H), 5.72 (dd,J = 10.6, 1.9 Hz, 1H), 4.85 (d, J = 7.3 Hz, 1H), 4.78-4.68 (m, 1H),4.52- 3.86 (m, 5H), 3.73-3.33 (m, 2H), 3.20-2.92 (m, 3H), 1.35 (d, J =6.7 Hz, 1H), 1.30 (d, J = 6.7 Hz, 1H) 518.03 87.8 72 7-(7-acetyl-9-acryloyl-3,7,9- triazabicyclo[3.3.1] nonan-3-yl)-9-chloro- 10-(2,4-difluorophenyl)-2,3- dihydro-5H- [1,4]oxazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, MeOD) δ 8.45 (s, 1H), 7.62-7.52 (m, 1H), 7.25-7.15 (m,1H), 7.08- 6.90 (m, 2H), 6.76 (td, J = 16.5, 10.6 Hz, 1H), 6.27 (d, J =16.5 Hz, 1H), 5.78 (ddd, J = 10.6, 5.5, 1.9 Hz, 1H), 5.16- 5.03 (m, 1H),4.54-4.27 (m, 4H), 4.08 (dd, J = 13.3, 5.9 Hz, 1H), 4.01-3.79 (m, 2H),3.43-3.27 (m, 2H), 3.19- 2.99 (m, 3H), 2.77 (d, J = 16.1 Hz, 1H), 1.95(d, J = 11.1 Hz, 2H) 572.03 80.5 73 (S)-7-(4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-10-(3- chloro-5- fluorophenyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (400 MHz, CDCl₃) δ 7.47 (s, 1H), 7.23-7.20 (m, 1H), 7.07-7.05 (m,1H), 6.90- 6.88 (m, 1H), 6.59 (m, 1H), 6.40-6.35(dd, 1H), 5.80-5.77 (d,1H), 4.88-4.67 (m, 2H), 4.46-4.37 (m, 3H), 4.16-3.81 (m, 2H), 3.62-3.50(m, 2H), 3.13-3.08 (m, 3H), 1.49 (s, 1H). 519.42 73 747-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(2,3-difluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, MeOH- d₄) δ 7.69 (d, J = 8.3 Hz, 1H), 7.42 (q, J = 8.2Hz, 1H), 7.31 (td, J = 8.1, 8.0, 4.6 Hz, 1H), 7.06 (t, J = 6.3 Hz, 1H),6.91- 6.71 (m, 1H), 6.28 (dd, J = 16.8, 6.9 Hz, 1H), 5.80 (dd, J = 10.5,1.9 Hz, 1H), 4.84-4.74 (m, 1H), 4.60-3.95 (m, 5H), 3.78-3.42 (m, 2H),3.26-3.00 (m, 3H), 1.40 (dd, J = 20.2, 6.3 Hz, 3H) 502.96 95.6 757-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(2,4-difluorophenyl)-2,2- dimethyl-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

531.02 86.8 77 (2S)-1-acryloyl-4-(9- chloro-10-(2,4- difluorophenyl)-5-oxo-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-7-yl)piperazine-2- carbonitrile

1H NMR (400 MHz, CDCl₃) δ 7.76-7.68 (d, 1H), 7.26-7.17 (brs, 1H),7.06-6.97 (m, 2H), 6.61-6.45 (m, 2H), 5.93-5.90 (d, 1H), 4.65-4.36 (m,4H), 4.20-3.84 (m, 3H), 3.47-3.39 (t, 1H), 3.22-3.04 (m, 3H). 513.95 8278 (S)-9-chloro-10-(4- chloro-3- fluorophenyl)-7-(4-(2-fluoroacryloyl)-2- methylpiperazin-1- yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-3-one

1H NMR (400 MHz, CDCl₃) δ 7.54 (t, J = 8.0 Hz, 1H), 7.46 (s, 1H),7.08-7.04 (m, 1H), 7.00-6.97 (m, 1H), 5.42-5.30 (m, 1H), 5.22-5.17 (m,1H), 4.75 (br, 1H), 4.38-4.23 (m, 4H), 4.00-3.89 (m, 1H), 3.59- 3.54 (m,2H), 3.10-3.07 (m, 3H), 1.45-1.42 (m, 3H). 537.41 6.7 79(S,E)-9-chloro-10-(4- chloro-3- fluorophenyl)-7-(2- methyl-4-(4,4,4-trifluorobut-2- enoyl)piperazin-1- yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (400 MHz, CDCl₃) δ 7.54 (t, J = 8.0 Hz, 1H), 7.47- 7.45 (m, 1H),7.07-7.04 (m, 1H), 6.99-6.90 (m, 2H), 6.84- 6.76 (m, 1H), 4.88 (br,0.5H), 4.68-4.64 (m, 1H), 4.48-4.32 (m, 3H), 4.19-3.90 (m, 1H),3.52-3.74 (m, 2.5H), 3.19-2.97 (m, 3H), 1.45-1.40 (m, 3H). 587.42 92 80(S,E)-9-chloro-10-(4- chloro-3- fluorophenyl)-7-(4- (4,4-difluorobut-2-enoyl)-2- methylpiperazin-1- yl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

1H NMR (400 MHz, CDCl₃) δ 7.54 (t, J = 7.6 Hz, 1H), 7.47- 7.45 (m, 1H),7.07-7.04 (m, 1H), 6.99-6.97 (m, 1H), 6.82- 6.71 (m, 2H), 6.42-6.15 (m,1H), 4.87 (br, 0.5H), 4.68-4.65 (m, 1H), 4.47-4.29 (m, 3H), 4.18-3.92(m, 1H), 3.77-3.74 (m, 0.5H), 3.66-3.52 (m, 2H), 3.16-3.00 (m, 3H),1.45-1.39 (m, 3H). 569.43 93.5 81 2-((2S)-4-(9-chloro- 10-(2,4-difluorophenyl)-5- oxo-2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-1- ((E)-4,4,4- trifluorobut-2- enoyl)piperazin-2-yl)acetonitrile

1H NMR (400 MHz, CDCl₃) δ 7.59(s, 1H), 7.28-7.21 (m, 1H), 7.11-7.00 (m,3H), 6.92- 6.80 (m, 1H), 5.14(s, 0.6H), 4.74-4.63(m, 1H), 4.45-4.37 (m,3H), 4.22-3.79(m, 3H), 3.60-3.49(m, 1.4H), 3.17- 3.14(t, 2H),3.00-2.80(m, 2H). 595.97 89 82 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(5- chloro-2,4- difluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, MeOD) δ 8.45 (s, 1H), 7.59 (d, J = 7.3 Hz, 1H),7.44-7.35 (m, 1H), 7.28 (t, J = 9.2 Hz, 1H), 6.79- 6.65 (m, 1H), 6.18(dd, J = 16.8, 7.0 Hz, 1H), 5.71 (dd, J = 10.6, 1.9 Hz, 1H), 4.69 (s,1H), 4.51-3.87 (m, 5H), 3.65- 3.35 (m, 2H), 3.20-2.83 (m, 4H), 1.30 (dd,J = 17.4, 6.7 Hz, 2H). 537.41 85.8 83 (S)-5-(7-(4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-5-oxo- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-10-yl)- 2-fluorobenzonitrile

¹H NMR (400 MHz, MeOD) δ 8.45 (s, 1H), 7.73-7.49 (m, 3H), 7.45 (t, J =8.9 Hz, 1H), 6.82-6.65 (m, 1H), 6.19 (dd, J = 16.9, 7.1 Hz, 1H), 5.71(dd, J = 10.5, 1.9 Hz, 1H), 4.73 (s, 1H), 4.46-3.91 (m, 5H), 3.48 (dt, J= 67.1, 13.4 Hz, 2H), 3.20-2.86 (m, 4H), 1.30 (d, J = 6.7 Hz, 2H).509.98 85.3 84 85 (S)-5-(7-(4-acryloyl- 2-methylpiperazin-1-yl)-9-chloro-5-oxo- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-10-yl)- 2-fluoro-N- methylbenzamide

¹H NMR (400 MHz, MeOD) δ 7.62-7.51 (m, 2H), 7.37- 7.23 (m, 2H),6.80-6.64 (m, 1H), 6.18 (dd, J = 16.8, 6.9 Hz, 1H), 5.71 (dd, J = 10.6,2.0 Hz, 1H), 4.73 (s, 1H), 4.49- 3.89 (m, 6H), 3.59-3.36 (m, 2H),3.18-2.89 (m, 4H), 2.85 (s, 3H), 1.30 (dd, J = 6.8, 2.5 Hz, 2H). 542.0260.3 86 7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(isoquinolin-5-yl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, MeOD) δ 9.26 (s, 1H), 8.63-8.24 (m, 2H), 8.17 (d, J =8.2 Hz, 1H), 7.80-7.47 (m, 3H), 7.23 (d, J = 5.8 Hz, 1H), 6.74 (ddd, J =21.1, 16.7, 10.6 Hz, 1H), 6.26- 6.13 (m, 1H), 5.72 (dd, J = 10.6, 1.9Hz, 1H), 4.61-3.86 (m, 6H), 3.68-3.39 (m, 2H), 3.17-2.93 (m, 3H), 1.34(dd, J = 15.2, 6.7 Hz, 2H). 518.03 76.1 88 2-((2S)-1-acryloyl-4-(9-chloro-10-(2,4- difluorophenyl)-5- oxo-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-7- yl)piperazin-2- yl)acetonitrile

1H NMR (400 MHz, CDCl₃) δ 7.55 (m, 1H), 7.26-7.17 (m, 1H), 7.05-6.96 (m,2H), 6.62- 6.55 (m, 1H), 6.42-6.38(m, 1H), 5.85-5.83 (m, 1H), 5.03- 4.97(m, 1H), 4.67-4.64(m, 1H), 4.4-4.09(m, 3H), 4.02- 4.01(m, 1H),3.76-3.66(m, 2H), 3.54-3.43(m, 1H), 3.14- 3.09(m, 2H), 2.94-2.75(m, 2H).527.97 90.2 89 (S)-7-(4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(4- chloro-3- fluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (400 MHz, CDCl₃) δ 7.54 (t, J = 7.6 Hz, 1H), 7.47 (m, 1H),7.08-7.04 (m, 1H), 6.99-6.97 (m, 1H), 6.66-6.52 (m, 1H), 6.39-6.35 (m,1H), 5.78 (d, J = 11.2 Hz, 1H), 4.89- 4.88 (m, 0.5H), 4.70-4.66 (m, 1H),4.45-4.32 (m, 3H), 4.17- 3.94 (m, 1H), 3.85-3.78 (m, 0.5H), 3.61-3.50(m, 2H), 3.14-2.90 (m, 3H), 1.41 (s, 3H). 519.42 94.5 90(S)-7-(4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10- (3,4,5-trifluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

1H NMR (400 MHz, CDCl₃) δ 7.46 (s, 1H), 6.89 (s, 2H), 6.67-6.63 (m, 1H),6.49-6.39 (m, 1H), 5.80-5.77 (m, 1H), 4.89-4.86 (m, 0.5H), 4.72-4.60 (m,1H), 4.49-4.33 (m, 3H), 4.15-3.97 (m, 1H), 3.84-3.82 (m, 0.5H),3.65-3.50 (m, 2H), 3.11-2.88 (m, 3H), 1.41 (s, 3H). 520.95 78.8 93(S,E)-9-chloro-10-(3- chloro-4- fluorophenyl)-7-(2- methyl-4-(4,4,4-trifluorobut-2- enoyl)piperazin-1- yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (400 MHz, CDCl₃) δ 7.47-7.45 (m, 1H), 7.31-7.29 (m, 2H),7.14-7.12 (m, 1H), 7.04-6.91 (m, 1H), 6.86-6.76 (m, 1H), 4.87 (s, 0.5H),4.68- 4.64 (m, 1H), 4.48-4.29 (m, 3H), 3.93-3.90 (m, 0.5H), 3.74-3.71(m, 0.5H), 3.68-3.53 (m, 3H), 3.17-3.15 (m, 0.5H), 3.13-3.02 (m, 2H),1.50-1.38 (m, 3H). 587.42 95 95 7-(9-acryloyl-7- (methylsulfonyl)-3,7,9- triazabicyclo[3.3.1] nonan-3-yl)-9-chloro- 10-(2,4-difluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, MeOD) δ 7.59 (s, 1H), 7.25-7.15 (m, 1H), 7.08-6.97 (m,2H), 6.79- 6.68 (m, 1H), 6.25 (dd, J = 16.7, 1.8 Hz, 1H), 5.77 (dd, J =10.6, 1.9 Hz, 1H), 4.98- 4.84 (m, 1H), 4.76 (s, 1H), 4.48-4.40 (m, 1H),4.26- 3.94 (m, 3H), 3.77-3.55 (m, 4H), 3.04 (h, J = 3.3 Hz, 2H),2.97-2.79 (m, 2H), 2.55 (s, 3H). 608.08 70.5 96 7-((S)-4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-10-(3- oxoisoindolin-4-yl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, MeOH- d₄) δ 7.78-7.67 (m, 2H), 7.63 (d, J = 9.4 Hz,1H), 7.27 (d, J = 5.3 Hz, 1H), 6.92-6.72 (m, 1H), 6.29 (dd, J = 15.6,5.2 Hz, 1H), 5.81 (d, J = 10.6 Hz, 1H), 4.86-4.75 (m, 1H), 4.60- 3.95(m, 5H), 4.51 (s, 2H, overlap), 3.78-3.39 (m, 2H), 3.23-2.98 (m, 3H),1.40 (dd, J = 23.6, 6.7 Hz, 3H) 522.02 54 98 (S)-7-(4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-10-(3- chloro-4- fluorophenyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (400 MHz, CDCl₃) δ 7.47 (s, 1H), 7.30-7.28 (m, 2H), 6.63-6.52 (m,1H), 6.40- 6.35 (m, 1H), 5.79 (d, J = 11.6 1H), 4.88-4.87 (m, 1H),4.70-4.63 (m, 1H), 4.45-4.33 (m, 3H), 4.13-4.12 (m, 1H), 3.83-3.79 (m,0.5H), 3.62- 3.51(m, 2H), 3.11-2.95 (m, 3H), 1.58-1.25 (m, 3H). 519.4286.4 99 (3R)-7-((S)-4- acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-3- methyl-2,3-dihydro- 5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (400 MHz, CDCl₃) δ 7.51 (s, 1H), 7.25-7.19 (m, 1H), 7.07-6.97 (m,2H), 6.59- 6.57 (m, 1H), 6.39-6.36(d, 1H), 5.79-5.76(d, 1H), 5.42(s,1H), 4.96-4.86(d, 1H), 4.64- 4.62(d, 1H), 4.02-3.96(t, 1.5H),3.83-3.67(m, 2H), 3.42-3.21(m, 2H), 2.92- 2.87(m, 1.5H), 1.48-1.45(t,3H), 1.33-1.31(d, 3H). 516.99 87.2 105 7-((S)-4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-10-(2- oxoindolin-4-yl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, MeOH- d₄) δ 7.68 (d, J = 4.5 Hz, 1H), 7.36 (t, J = 7.8Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 6.91-6.75 (m, 2H), 6.29 (dd, J =16.8, 5.7 Hz, 1H), 5.81 (dd, J = 10.6, 1.9 Hz, 1H), 4.85-4.76 (m, 1H),4.65-3.98 (m, 5H), 3.75-3.43 (m, 2H), 3.31 (s, overlapped with D₃COH,2H), 3.30-3.05 (m, 4H), 1.41 (dd, J = 11.0, 6.7 Hz, 3H) 522.02 18.9 106(S)-7-(4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(4- chloro-2,6-difluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, MeOH- d₄) δ 8.52 (br s, 1H), 7.71 (s, 1H), 7.31 (d, J =7.6 Hz, 2H), 6.82 (ddd, J = 21.7, 16.7, 10.6 Hz, 1H), 6.28 (dd, J =17.1, 6.7 Hz, 1H), 5.81 (dd, J = 10.6, 2.0 Hz, 1H), 4.60-3.96 (m, 5H),3.74-3.55 (m, 3H), 3.27-3.18 (m, 3H), 1.41 (d, J = 6.8 Hz, 3H) 537.4145.2 107 (S)-7-((S)-4-acryloyl- 2-methylpiperazin-1- yl)-9-chloro-10-(1-methyl-1H-indazol- 7-yl)-2,3-dihydro- 5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, DMSO) δ 8.14 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.68(s, 1H), 7.26 (t, J = 7.4 Hz, 1H), 7.17 (s, 1H), 6.85 (dd, J = 27.2,16.7 Hz, 1H), 6.20 (d, J = 15.8 Hz, 1H), 5.75 (d, J = 10.2 Hz, 1H), 4.70(s, 1H), 4.45-4.22 (m, 2H), 4.11 (d, J = 39.6 Hz, 3H), 3.56 (s, 5H),3.15 (s, 2H), 3.01 (s, 1H), 1.28 (s, 3H). 521.03 0 108 (R)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(1- methyl-1H-indazol-7-yl)-2,3-dihydro- 5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, DMSO) δ 8.14 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.68(s, 1H), 7.26 (t, J = 7.4 Hz, 1H), 7.17 (s, 1H), 6.85 (dd, J = 27.2,16.7 Hz, 1H), 6.20 (d, J = 15.8 Hz, 1H), 5.75 (d, J = 10.2 Hz, 1H), 4.70(s, 1H), 4.45-4.22 (m, 2H), 4.11 (d, J = 39.6 Hz, 3H), 3.56 (s, 5H),3.15 (s, 2H), 3.01 (s, 1H), 1.28 (s, 3H). 521.03 91.7 111(S,E)-9-chloro-7-(2- methyl-4-(4,4,4- trifluorobut-2- enoyl)piperazin-1-yl)-10-(2,4,6- trifluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

1H NMR (400 MHz, CDCl₃) δ 7.49-7.47 (d, 1H), 7.04-6.90 (m, 1H),6.86-6.76 (m, 3H), 4.87-4.48 (m, 2H), 4.45- 4.16(m, 3H), 3.93-3.50(m,3H), 3.18-3.00(m, 3H), 1.45- 1.40(m, 3H). 588.95 95.2 1129-chloro-10-(2,4- difluorophenyl)-7- ((S)-2-methyl-4-((E)-4,4,4-trifluorobut-2- enoyl)piperazin-1- yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (400 MHz, CDCl₃) δ 7.48-7.46 (brs, 1H), 7.24-7.17 (brs, 1H),7.06-6.91 (m, 3H), 6.84-6.76 (m, 1H), 4.93- 4.75(m, 1H), 4.71-4.55(m,1H), 4.53-4.42(m, 1H), 4.39- 4.10(m, 2H), 3.93-3.47(brs, 3H),3.21-2.96(m, 3H), 1.53- 1.38(m, 3H). 570.96 86.2 113 9-chloro-10-(2,4-difluorophenyl)-7- ((S)-4-(2- fluoroacryloyl)-2- methylpiperazin-1-yl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (400 MHz, CDCl₃) δ 7.47 (d, 1H), 7.21-7.19 (m, 1H), 7.05-6.97 (m,2H), 5.42- 5.29 (m, 1H), 5.22-5.17(m, 1H), 4.83-4.72(brs, 1H),4.56-4.45(brs, 1H), 4.45- 4.11(brs, 3H), 4.09-3.88(brs, 1H),3.67-3.42(brs, 2H), 3.11-3.09(t, 3H), 1.47- 1.40(m, 3H). 520.95 21.7 1199-chloro-7-((S)-4- ((E)-4,4-difluorobut- 2-enoyl)-2- methylpiperazin-1-yl)-10-(2,4- difluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

1H NMR (400 MHz, CDCl₃) δ 7.47 (brs, 1H), 7.23-7.17 (m, 1H), 7.06-6.96(m, 2H), 6.83- 6.70 (m, 2H), 6.43-6.75(t, 1H), 4.93-4.57(m, 2H), 4.53-4.10(m, 3H), 3.95-3.48(m, 3H), 3.20-2.97(m, 3H), 1.59- 1.38(m, 3H).552.97 97.1 120 (S,E)-9-chloro-7-(4- (4,4-difluorobut-2- enoyl)-2-methylpiperazin-1- yl)-10-(2,4,6- trifluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.49-7.47 (m, 1H), 6.86-6.69 (m, 4H), 6.28 (t,J = 55.6 Hz, 1H), 4.87-4.65 (m, 1.5H), 4.48-4.32 (m, 3H), 4.19-4.15 (m,0.5H), 3.95-3.92 (m, 0.5H), 3.77-3.54 (m, 2.5H), 3.15-2.98 (m, 3H),1.45-1.40 (m, 3H). 570.96 95.9 121 (2S)-4-(9-chloro-10-(2,4-difluorophenyl)- 5-oxo-2,3-dihydro- 5H- [1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-1- ((E)-4- (dimethylamino)but- 2-enoyl)piperazine-2-carbonitrile

1H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 7.59-7.37 (m, 1H), 7.27 (dd, J =22.3, 16.0 Hz, 1H), 6.75 (ddd, J = 43.5, 17.4, 10.3 Hz, 1H), 5.32 (p, J= 10.8 Hz, 1H), 4.43 (dd, J = 31.3, 19.2 Hz, 1H), 4.31- 4.14 (m, 1H),4.14-3.94 (m, 1H), 3.71 (s, 1H), 3.60 (s, 2H), 3.09 (d, J = 5.8 Hz, 2H),2.21 (d, J = 27.5 Hz, 2H), 2.09- 1.91 (m, 2H), 1.44 (dd, J = 17.1, 7.1Hz, 2H), 1.24 (s, 6H). 571.04 3.6 123 (R)-7-((S)-4- acryloyl-2-methylpiperazin-1- yl)-9-chloro-10-(2- fluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, DMSO- d₆) δ 7.64 (s, 1H), 7.47-7.61 (m, 1H), 7.23-7.44(m, 3H), 6.68-6.94 (m, 1H), 6.18 (dd, J = 7.07, 16.45 Hz, 1H), 5.74 (dd,J = 2.31, 10.44 Hz, 1H), 4.69 (br. s., 1H), 4.40 (d, J = 11.63 Hz, 1H),4.27 (d, J = 12.51 Hz, 2H), 4.12 (d, J = 12.38 Hz, 1H), 4.00 (d, J =12.88 Hz, 3H), 3.57 (br. s., 1H), 3.05-3.24 (m, 2H), 1.25 (d, J = 6.50Hz, 3H) 484.97 91.3 124 (S)-7-((S)-4-acryloyl- 2-methylpiperazin-1-yl)-9-chloro-10-(2- fluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, DMSO- d₆) δ 7.50-7.74 (m, 2H), 7.20- 7.44 (m, 3H),6.72-7.01 (m, 1H), 6.18 (dd, J = 6.00, 16.51 Hz, 1H), 5.66-5.80 (m, 1H),4.63 (br. s., 1H), 4.41 (d, J = 12.63 Hz, 1H), 4.17-4.34 (m, 1H),3.89-4.13 (m, 3H), 3.54 (d, J = 9.51 Hz, 1H), 3.10- 3.21 (m, 3H),3.07-2.88 (m, 1H), 1.22-1.35 (m, 3H) 484.97 96 125 (2S)-4-(9-chloro-10-(2,4-difluorophenyl)- 5-oxo-2,3-dihydro- 5H- [1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-1- (2- fluoroacryloyl) piperazine- 2-carbonitrile

1H NMR (400 MHz,) δ 7.78 (d, J = 11.2 Hz, 1H), 7.49 (td, J = 9.7, 2.4Hz, 1H), 7.45- 7.37 (m, 1H), 7.28 (td, J = 8.5, 2.4 Hz, 1H), 5.59 (d, J= 10.9 Hz, 1H), 5.54 (q, J = 4.4 Hz, 1H), 5.46 (dd, J = 37.9, 4.3 Hz,1H), 4.54-4.42 (m, 1H), 4.37 (ddd, J = 13.7, 5.8, 2.5 Hz, 0.5H),4.30-4.04 (m, 3H), 3.98 (ddd, J = 13.9, 8.9, 2.6 Hz, 0.5H), 3.68 (dd, J= 14.1, 3.5 Hz, 1H), 3.60 (dd, J = 14.2, 3.6 Hz, 1H), 3.28- 3.06 (m,3H). 531.94 94.5 127 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(1- methyl-1H-indazol- 7-yl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, DMSO) δ 8.14 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.68(s, 1H), 7.26 (t, J = 7.4 Hz, 1H), 7.17 (s, 1H), 6.85 (dd, J = 27.2,16.7 Hz, 1H), 6.20 (d, J = 15.8 Hz, 1H), 5.75 (d, J = 10.2 Hz, 1H), 4.70(s, 1H), 4.45-4.22 (m, 2H), 4.11 (d, J = 39.6 Hz, 3H), 3.56 (s, 5H),3.15 (s, 2H), 3.01 (s, 1H), 1.28 (s, 3H). 521.03 60 130 (3R)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(2,4- difluorophenyl)-3-(methoxymethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

547.02 94.5 134 7-(4- acryloylhexahydro- furo[3,4-b]pyrazin-1(2H)-yl)-9-chloro- 10-(2,4- difluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, MeOD) δ 7.64 (d, J = 13.5 Hz, 1H), 7.26- 7.15 (m, 1H),7.10-6.97 (m, 2H), 6.78-6.61 (m, 1H), 6.17 (dd, J = 16.7, 1.9 Hz, 1H),5.70 (dd, J = 10.5, 2.0 Hz, 1H), 4.97-4.82 (m, 2H), 4.40-4.18 (m, 2H),4.14- 3.41 (m, 8H), 3.16-3.01 (m, 2H) 530.97 85 135 7-(3-acryloyl-3,6-diazabicyclo[3.1.1] heptan-6-yl)-9-chloro- 10-(2,4- difluorophenyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, MeOD) δ 7.98 (d, J = 22.3 Hz, 1H), 7.19 (tdd, J = 8.7,6.3, 1.9 Hz, 1H), 7.09-6.94 (m, 2H), 6.79- 6.60 (m, 1H), 6.17-6.02 (m,1H), 5.75-5.54 (m, 1H), 4.78- 4.26 (m, 4H), 4.19-4.03 (m, 2H), 3.70-3.35(m, 2H), 3.11-2.96 (m, 2H), 2.45- 2.16 (m, 2H) 500.95 0 1367-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(2-oxopyridin-1(2H)- yl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

1H NMR (400 MHz, DMSO) δ 8.09 (d, J = 4.7 Hz, 1H), 7.93 (t, J = 7.7 Hz,1H), 7.62 (s, 1H), 7.27-7.13 (m, 2H), 7.01-6.65 (m, 1H), 6.18 (dd, J =15.8, 7.0 Hz, 1H), 5.74 (d, J = 10.4 Hz, 1H), 4.63 (s, 1H), 4.33 (dd, J= 56.3, 12.7 Hz, 1H), 4.23-4.07 (m, 2H), 4.01 (d, J = 12.4 Hz, 2H), 3.55(d, J = 12.7 Hz, 2H), 3.15 (d, J = 24.1 Hz, 2H), 2.98 (d, J = 12.5 Hz,1H), 1.26 (d, J = 5.7 Hz, 3H). 483.97 89.4 137 (R)-7-((S)-4- acryloyl-2-methylpiperazin-1- yl)-9-chloro-3- (methoxymethyl)-10- (2,4,6-trifluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

565.01 86.8 145 7-(5-acryloyl-2,5- diazabicyclo[4.2.0]octan-2-yl)-9-chloro- 10-(2,4- difluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, MeOD) δ 7.67 (d, J = 1.8 Hz, 1H), 7.28- 7.13 (m, 1H),7.09-6.91 (m, 2H), 6.34 (dd, J = 16.8, 10.3 Hz, 1H), 6.19 (dd, J = 16.8,2.1 Hz, 1H), 5.67 (dd, J = 10.2, 2.1 Hz, 1H), 4.69- 4.45 (m, 1H),4.36-4.26 (m, 1H), 4.24-4.07 (m, 2H), 4.04- 3.90 (m, 2H), 3.85-3.71 (m,1H), 3.71-3.57 (m, 1H), 3.16-2.94 (m, 2H), 2.48- 2.22 (m, 2H), 2.01-1.83(m, 1H), 1.68-1.52 (m, 1H) 514.97 58 146 (S)-7-(4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-10- (2,4,6- trifluorophenyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, DMSO) δ 7.67 (s, 1H), 7.47 (t, J = 8.8 Hz, 2H),6.94-6.70 (m, 1H), 6.18 (dd, J = 16.7, 6.4 Hz, 1H), 5.74 (dd, J = 10.4,2.0 Hz, 1H), 4.66 (s, 1H), 4.33 (dd, J = 54.2, 13.2 Hz, 1H), 4.22-3.91(m, 4H), 3.55 (d, J = 13.7 Hz, 2H), 3.22 (t, J = 4.9 Hz, 2H), 3.17-2.92(m, 1H), 1.26 (d, J = 6.4 Hz, 3H). 520.95 90.7 148 (R)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(2,4-difluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-3-one 1,1-dioxide

1H NMR (400 MHz, CDCl₃) δ 7.86 (s, 1H), 7.38-7.33 (m, 1H), 7.06-6.93 (m,2H), 6.60- 6.53 (m, 1H), 6.41-6.37, (m, 1H), 5.81-5.79 m, 1H), 5.05-5.01 2m, 1H), 4.78-4.71 (m, 1H), 4.59-4.35 (m, 3H), 4.01- 3.85 (m, 1H),3.62-3.44 (m, 4H), 3.04 (m, 1H), 1.45 (d, 3H). 534.96 95.9 149(S)-7-((S)-4-acryloyl- 2-methylpiperazin-1- yl)-9-chloro-10-(2,4-difluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1,1-dioxide

¹H NMR (400 MHz, CDCl₃) δ 7.87 (s, 1H), 7.37-7.31 (m, 1H), 7.05-6.93 (m,2H), 6.41- 6.37 (m, 1H), 6.35-6.31, (m, 1H), 5.81-5.79 m, 1H), 5.06-5.01 (m, 1.5H), 4.78-4.71 (m, 1H), 4.51-4.07 (m, 3H), 3.98- 3.44 (m,4.5H), 3.21-2.91 (m, 1H), 1.41 (s, 3H). 534.96 52.8 1507-((R)-4-acryloyl-2- (hydroxymethyl) piperazin-1-yl)-9- chloro-10-(2,4-difluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

1H NMR (400 MHz, DMSO) δ 7.90 (dd, J = 40.4, 14.2 Hz, 1H), 7.48 (td, J =9.7, 2.5 Hz, 1H), 7.44-7.36 (m, 1H), 7.27 (td, J = 8.5, 2.4 Hz, 1H),6.82 (ddd, J = 16.7, 10.5, 2.2 Hz, 1H), 6.16 (dd, J = 16.6, 2.1 Hz, 1H),5.72 (dd, J = 10.4, 2.2 Hz, 1H), 5.11 (dd, J = 11.5, 5.8 Hz, 1H), 4.53(s, 1H), 4.36-3.87 (m, 6H), 3.70- 3.38 (m, 4H), 3.23-3.01 (m, 2H).518.96 59.9 151 (S)-7-(4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(4- fluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

1H NMR (400 MHz, DMSO) δ 7.61 (s, 1H), 7.45-7.21 (m, 4H), 6.93-6.75 (m,1H), 6.18 (dd, J = 16.4, 7.3 Hz, 1H), 5.74 (dd, J = 10.4, 2.2 Hz, 1H),4.65 (s, 1H), 4.34 (dd, J = 55.7, 12.7 Hz, 1H), 4.04 (dd, J = 40.6, 26.7Hz, 4H), 3.54 (d, J = 14.0 Hz, 2H), 3.14 (t, J = 4.9 Hz, 2H), 2.96 (t, J= 11.7 Hz, 1H), 1.26 (d, J = 6.3 Hz, 3H). 484.97 94.1 1527-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(2- fluoro-5-hydroxyphenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (400 MHz, DMSO) δ 9.65 (s, 1H), 7.60 (d, J = 9.4 Hz, 1H), 7.17(t, J = 9.1 Hz, 1H), 6.92-6.74 (m, 2H), 6.59 (dt, J = 5.3, 2.5 Hz, 1H),6.18 (dd, J = 16.4, 6.0 Hz, 1H), 5.74 (dd, J = 10.4, 2.2 Hz, 1H), 4.65(d, J = 25.8 Hz, 1H), 4.47-4.17 (m, 2H), 4.16- 3.92 (m, 3H), 3.66-3.43(m, 1H), 3.24-3.06 (m, 3H), 2.96 (d, J = 12.7 Hz, 1H), 1.26 (dd, J =14.7, 6.1 Hz, 3H). 500.97 55.3 153 7-((S)-4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-10-(2- chloro-5- hydroxyphenyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (400 MHz, DMSO) δ 9.94 (s, 1H), 7.60 (s, 1H), 7.40 (d, J = 8.7Hz, 1H), 6.89 (dd, J = 8.7, 2.9 Hz, 1H), 6.81 (dd, J = 17.7, 10.0 Hz,1H), 6.62 (t, J = 2.6 Hz, 1H), 6.18 (dd, J = 16.4, 5.9 Hz, 1H), 5.74(dd, J = 10.4, 2.3 Hz, 1H), 4.65 (s, 1H), 4.46-3.94 (m, 5H), 3.67-3.47(m, 1H), 3.23-3.08 (m, 3H), 2.99 (d, J = 12.7 Hz, 1H), 1.25 (d, J = 6.7Hz, 3H). 517.43 55.7 154 (R)-7-((S)-4- acryloyl-2- methylpiperazin-1-yl)-9-chloro-10- (naphthalen-1-yl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, DMSO) δ 8.05 (t, J = 8.5 Hz, 2H), 7.66 (dd, J = 15.7,8.5 Hz, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.39(dd, J = 6.1, 3.3 Hz, 1H),7.35 (dd, J = 8.3, 3.6 Hz, 1H), 6.95-6.75 (m,1H), 6.26-6.11 (m, 1H), 5.75 (dd, J = 10.4, 2.3 Hz, 1H), 4.84-4.60 (m,1H), 4.49- 4.19 (m, 2H), 4.19-3.94 (m, 3H), 3.70-3.39 (m, 2H), 3.23-2.90(m, 3H), 1.37- 1.24 (m, 3H). 517.04 24 155 (S)-7-((S)-4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-10- (naphthalen-1-yl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, DMSO) δ 8.05 (t, J = 8.5 Hz, 2H), 7.66 (dd, J = 15.7,8.5 Hz, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.39(dd, J = 6.1, 3.3 Hz, 1H), 7.35 (dd, J = 8.3, 3.6 Hz, 1H), 6.95-6.75 (m,1H), 6.26-6.11 (m, 1H), 5.75 (dd, J = 10.4, 2.3 Hz, 1H), 4.84-4.60 (m,1H), 4.49- 4.19 (m, 2H), 4.19-3.94 (m, 3H), 3.70-3.39 (m, 2H), 3.23-2.90(m, 3H), 1.37- 1.24 (m, 3H). 517.04 92.2 159 7-((S)-4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-10-(5- methyl-1H-indazol-4-yl)-2,3-dihydro- 5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (400 MHz, DMSO) δ 13.11 (s, 1H), 7.66 (s, 1H), 7.57-7.47 (m, 2H),7.35 (d, J = 8.6 Hz, 1H), 6.93-6.75 (m, 1H), 6.19 (dd, J = 17.7, 6.2 Hz,1H), 5.75 (dd, J = 10.4, 2.3 Hz, 1H), 4.70 (s, 1H), 4.50- 4.21 (m, 1H),4.21-3.92 (m, 4H), 3.58 (s, 1H), 3.23- 2.86 (m, 4H), 2.12 (s, 3H), 1.29(d, J = 5.8 Hz, 3H). 521.03 37.2 160 7-((S)-4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-10-(2- fluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (400 MHz, DMSO) δ 7.68-7.52 (m, 2H), 7.47- 7.26 (m, 3H), 6.82 (s,1H), 6.18 (dd, J = 16.9, 7.0 Hz, 1H), 5.74 (dd, J = 10.4, 2.3 Hz, 1H),4.76-4.56 (m, 1H), 4.47-4.18 (m, 2H), 4.18- 3.92 (m, 3H), 3.66-3.42 (m,1H), 3.24-3.07 (m, 3H), 3.07- 2.88 (m, 1H), 1.26 (dd, J = 13.3, 6.8 Hz,3H). 484.97 72.7 161 (2R,5R)-4-acryloyl- 1-(9-chloro-10-(2,4-difluorophenyl)-5- oxo-2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-5- methylpiperazine-2- carbonitrile

¹H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 7.53 (td, J = 9.6, 2.2 Hz, 1H),7.41 (td, J = 14.5, 8.0 Hz, 1H), 7.36-7.28 (m, 1H), 6.92 (s, 1H), 6.39-6.13 (m, 1H), 5.87 (d, J = 10.9 Hz, 1H), 5.19 (d, J = 16.6 Hz, 1H), 4.88(dd, J = 22.7, 14.2 Hz, 1H), 4.61 (d, J = 10.7 Hz, 1H), 4.52-4.39 (m,1H), 4.38- 4.27 (m, 1H), 4.24-4.07 (m, 1H), 3.24-2.95 (m, 4H), 1.21 (s,3H). 527.97 1 162 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(5- (difluoromethyl)-2- fluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, DMSO) δ 7.89-7.71 (m, 1H), 7.65 (d, J = 10.2 Hz, 1H),7.62-7.53 (m, 2H), 7.12 (t, J = 55.6 Hz, 1H), 6.92-6.71 (m, 1H), 6.18(dd, J = 16.4, 6.3 Hz, 1H), 5.74 (dd, J = 10.4, 2.3 Hz, 1H), 4.78-4.54(m, 1H), 4.47- 4.18 (m, 2H), 4.18-3.88 (m, 3H), 3.56 (d, J = 11.6 Hz,2H), 3.27-3.08 (m, 2H), 3.05 2.89 (m, 1H), 1.26 (dd, J = 13.8, 6.5 Hz,3H). 534.98 39 163 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(5- (difluoromethoxy)-2- fluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (400 MHz, DMSO) δ 7.64 (d, J = 8.1 Hz, 1H), 7.50 (t, J = 8.9 Hz,1H), 7.42- 7.36 (m, 1H), 7.27 (t, J = 73.6 Hz, 1H), 7.20 (td, J = 5.5,3.0 Hz, 1H), 6.91-6.72 (m, 1H), 6.18 (dd, J = 15.9, 6.3 Hz, 1H), 5.74(dd, J = 10.4, 2.3 Hz, 1H), 4.75-4.54 (m, 1H), 4.46-4.18 (m, 2H), 4.17-3.90 (m, 3H), 3.67-3.43 (m, 2H), 3.25-3.07 (m, 2H), 3.05 2.87 (m, 1H),1.26 (dd, J = 10.3, 6.8 Hz, 3H). 550.98 41.4 165 7-(6-acryloyl-3,6-diazabicyclo[3.1.1] heptan-3-yl)-9- chloro-10-(2,4- difluorophenyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, MeOD) δ 7.93 (d, J = 1.1 Hz, 1H), 7.25- 7.15 (m, 1H),7.09-6.93 (m, 2H), 6.39 (dd, J = 16.9, 10.3 Hz, 1H), 6.20 (dt, J = 16.9,1.7 Hz, 1H), 5.69 (dd, J = 10.3, 1.8 Hz, 1H), 4.51- 4.04 (m, 7H), 3.07(dd, 2H), 2.69 (q, J = 6.6 Hz, 1H), 1.61 (d, J = 9.1 Hz, 1H) 500.95 16.9167 7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(2-(trifluoromethyl) phenyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

1H NMR (400 MHz, DMSO) δ 7.92 (d, J = 8.0 Hz, 1H), 7.84 (t, J = 7.5 Hz,1H), 7.73 (t, J = 7.6 Hz, 1H), 7.63 (s, 1H), 7.41-7.26 (m, 1H), 6.95-6.75 (m, 1H), 6.25-6.13 (m, 1H), 5.74 (dd, J = 10.4, 2.3 Hz, 1H),4.77-4.57 (m, 1H), 4.47-4.22 (m, 1H), 4.21- 3.95 (m, 4H), 3.66-3.37 (m,2H), 3.20-3.08 (m, 2H), 3.05-2.91 (m, 1H), 1.26 (d, J = 6.8 Hz, 3H).534.98 69.8 168 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2- fluoro-6- hydroxyphenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, DMSO) δ 10.08-10.05 (m, 1H), 7.59 (s, 1H), 7.31 (dd, J= 15.4, 8.3 Hz, 1H), 6.88-6.69 (m, 3H), 6.23-6.11 (m, 1H), 5.74 (dd, J =10.4, 2.3 Hz, 1H), 4.71- 4.56 (m, 1H), 4.45-4.23 (m, 1H), 4.21-3.91 (m,4H), 3.60- 3.45 (m, 2H), 3.16-3.11 (m, 2H), 3.03-2.90 (m, 1H), 1.26 (d,J = 6.0 Hz, 3H). 500.97 30.6 169 7-((S)-4-acryloyl-2- (azetidin-1-ylmethyl)piperazin- 1-yl)-9-chloro-10- (2,4-difluorophenyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, DMSO) δ 8.01 (d, J = 57.6 Hz, 1H), 7.56-7.44 (m, 1H),7.40 (dd, J = 14.6, 7.8 Hz, 1H), 7.28 (td, J = 8.5, 2.5 Hz, 1H), 6.82(d, J = 9.7 Hz, 1H), 6.17 (d, J = 16.8 Hz, 1H), 5.74 (s, 1H), 4.47-4.24(m, 3H), 4.16- 4.01 (m, 3H), 3.40 (dd, J = 12.4, 5.9 Hz, 1H), 3.35 (s,1H), 3.30 (s, 1H), 3.15 (dd, J = 42.2, 31.1 Hz, 7H), 2.88 (dd, J = 21.5,10.7 Hz, 1H), 1.93 (s, 2H). 558.04 23.3 170 (S)-7-(4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-10-(2,6- difluorophenyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, DMSO) δ 7.71-7.61 (m, 2H), 7.32 (t, J = 8.4 Hz, 2H),6.90-6.75 (m, 1H), 6.23-6.12 (m, 1H), 5.74 (dd, J = 10.4, 2.3 Hz, 1H),4.74-4.60 (m, 1H), 4.45- 3.95 (m, 5H), 3.64-3.48 (m, 2H), 3.21 (t, J =5.1 Hz, 2H), 3.17-2.92 (m, 1H), 1.27 (d, J = 6.5 Hz, 3H). 502.96 75.9171 7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(2,5-dichlorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, DMSO) δ 7.71 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 4.1 Hz,1H), 7.61 (dd, J = 8.7, 2.6 Hz, 1H), 7.48 (dd, J = 6.3, 2.5 Hz, 1H),6.90- 6.77 (m, 1H), 6.18 (dd, J = 17.3, 7.9 Hz, 1H), 5.74 (dd, J = 10.4,2.3 Hz, 1H), 4.67 (s, 1H), 4.45-3.95 (m, 5H), 3.64 3.48 (m, 2H),3.25-3.11 (m, 2H), 3.07-2.91 (m, 1H), 1.26 (d, J = 6.3 Hz, 3H). 535.8748.9 172 7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(naphthalen-1-yl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, DMSO) δ 8.05 (t, J = 8.5 Hz, 2H), 7.66 (dd, J = 15.7,8.5 Hz, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.39(dd, J = 6.1, 3.3 Hz, 1H), 7.35 (dd, J = 8.3, 3.6 Hz, 1H), 6.95-6.75 (m,1H), 6.26-6.11 (m, 1H), 5.75 (dd, J = 10.4, 2.3 Hz, 1H), 4.84-4.60 (m,1H), 4.49- 4.19 (m, 2H), 4.19-3.94 (m, 3H), 3.70-3.39 (m, 2H), 3.23-2.90(m, 3H), 1.37- 1.24 (m, 3H). 517.04 51.9 173 (2R)-4-acryloyl-1-(9-chloro-10-(2,4- difluorophenyl)-5- oxo-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-7- yl)piperazine-2- carbonitrile

¹H NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 7.53 (td, J = 9.6, 2.3 Hz, 1H),7.44-7.37 (m, 1H), 7.36-7.26 (m, 1H), 6.91 (s, 1H), 6.27 (d, J = 16.0Hz, 1H), 5.86 (d, J = 11.0 Hz, 1H), 4.83 (d, J = 8.6 Hz, 2H), 4.61-4.48(m, 1H), 4.35- 4.00 (m, 3H), 3.03-2.78 (m, 5H). 513.95 2.2 1747-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(3- chloro-2-fluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (400 MHz, DMSO) δ 7.79-7.73 (m, 1H), 7.65 (d, J = 8.4 Hz, 1H),7.42 (t, J = 7.9 Hz, 1H), 7.33 (dddd, J = 7.8, 6.3, 4.6, 1.7 Hz, 1H),6.94- 6.75 (m, 1H), 6.18 (dd, J = 16.8, 6.3 Hz, 1H), 5.74 (dd, J = 10.4,2.3 Hz, 1H), 4.66 (d, J = 25.0 Hz, 1H), 4.45-4.19 (m, 2H), 4.18-3.91 (m,3H), 3.51 (dd, J = 43.2, 15.1 Hz, 2H), 3.26-3.09 (m, 2H), 2.97 (dd, J =24.1, 11.9 Hz, 1H), 1.26 (dd, J = 12.0, 6.6 Hz, 3H). 519.42 93.8 1757-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(5- chloro-2-fluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

1H NMR (401 MHz, DMSO) δ 7.64 (d, J = 10.8 Hz, 2H), 7.55-7.41 (m, 2H),6.83 (d, J = 10.2 Hz, 1H), 6.30-6.06 (m, 1H), 5.74 (dd, J = 10.4, 2.0Hz, 1H), 4.65 (d, J = 31.4 Hz, 1H), 4.47-4.18 (m, 2H), 4.03 (dd, J =27.6, 13.3 Hz, 3H), 3.68-3.41 (m, 2H), 3.27- 3.07 (m, 2H), 3.06-2.87 (m,1H), 1.26 (dd, J = 12.9, 6.2 Hz, 3H). 519.42 79.8 1762-((2S)-4-(9-chloro- 10-(2,4- difluorophenyl)-5- oxo-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-7-yl)-1- (2- fluoroacryloyl)piper-azin-2-yl)acetonitrile

¹H NMR (400 MHz, DMSO) δ 7.85 (d, J = 15.6 Hz 1H), 7.54-7.36 (m, 2H),7.29 (td, J = 8.5, 2.4 Hz, 1H), 5.42 (dd, J = 17.9, 4.0 Hz, 1H), 5.31(d, J = 50.2 Hz, 1H), 4.88 (s, 1H), 4.45-4.35 (m, 1H), 4.26 (d, J = 13.8Hz, 1H), 4.19 (d, J = 10.7 Hz, 2H), 3.93 (dd, J = 12.0, 8.8 Hz, 1H),3.35-3.08 (m, 6H), 3.02 (dd, J = 17.1, 5.7 Hz, 1H). 545.96 40.5 177(S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1,1-dioxide

¹H NMR (400 MHz, DMSO) δ 8.21-8.03 (m, 1H), 7.49- 7.34 (m, 2H), 7.24(td, J = 8.5, 2.3 Hz, 1H), 6.89-6.71 (m, 1H), 6.17 (dd, J = 16.7, 2.2Hz, 1H), 5.74 (ddd, J = 10.4, 5.0, 2.2 Hz, 1H), 4.82-4.34 (m, 3H),4.27-3.97 (m, 2H), 3.96-3.48 (m, 5H), 1.41- 1.03 (m, 6H). 548.99 93.5178 (R)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1,1-dioxide

¹H NMR (400 MHz, DMSO) δ 8.21-8.03 (m, 1H), 7.49- 7.34 (m, 2H), 7.24(td, J = 8.5, 2.3 Hz, 1H), 6.89-6.71 (m, 1H), 6.17 (dd, J = 16.7, 2.2Hz, 1H), 5.74 (ddd, J = 10.4, 5.0, 2.2 Hz, 1H), 4.82-4.34 (m, 3H),4.27-3.97 (m, 2H), 3.96-3.48 (m, 5H), 1.41- 1.03 (m, 6H). 548.99 58.3179 (S)-7-((S)-4-acryloyl- 2-methylpiperazin-1- yl)-9-chloro-10-(2,4-difluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

1H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.24-7.18 (m, 1H), 7.06-6.96 (m,2H), 6.66- 6.52 (m, 1H), 6.38 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.78 (d, J= 10.8 Hz, 1H), 4.83-4.48 (m, 3H), 4.41-4.20 (m, 2H), 4.00-3.48 (m, 3H),3.12-2.97 (m, 3H), 1.48-1.46 (m, 3H). 502.96 96 180 (R)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(2,4-difluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.23-7.17 (m, 1H), 7.06-6.96 (m,2H), 6.66- 6.51 (m, 1H), 6.38 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.78 (d, J= 12.0 Hz, 1H) 4.95-4.45 (m, 3H), 4.34-3.98 (m, 3H), 3.80-3.47 (m, 2H),3.17-2.91 (m, 3H), 1.39-1.38 (m, 3H). 502.96 94.7 181 7-(5-acryloyl-2,5-diazabicyclo[2.2.2] octan-2-yl)-9-chloro- 10-(2,4- difluorophenyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, MeOD) δ 7.84-7.69 (m, 1H), 7.20 (dtd, J = 10.5, 8.5,6.3 Hz, 1H), 7.04 (qd, J = 6.8, 2.6 Hz, 2H), 6.60 (dddd, J = 44.5, 16.8,10.5, 3.6 Hz, 1H), 6.27-6.13 (m, 1H), 5.77-5.62 (m, 1H), 4.93 (s, 1H),4.70 (t, J = 2.9 Hz, 1H), 4.43 (ddt, J = 14.4, 6.1, 3.1 Hz, 1H),4.23-3.63 (m, 5H), 3.14-2.98 (m, 2H), 2.37-2.21 (m, 1H), 2.04- 1.77 (m,3H) 514.97 28.7 182 7-(9-acryloyl-3-oxa- 7,9- diazabicyclo[3.3.1]nonan-7-yl)-9-chloro- 10-(2,4- difluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, MeOD) δ 7.65 (s, 1H), 7.20 (td, J = 8.5, 6.3 Hz, 1H),7.09-6.98 (m, 2H), 6.72 (m, 1H), 6.25 (dd, J = 16.8, 1.9 Hz, 1H), 5.76(dd, J = 10.5, 1.9 Hz, 1H), 4.92- 4.80 (m, 1H), 4.71 (ddt, J = 16.8,13.3, 1.9 Hz, 1H), 4.55- 4.48 (m, 1H), 4.37-4.26 (m, 1H), 4.21 (s, 1H),4.12-3.89 (m, 3H), 3.78-3.70 (m, 1H), 3.63 (m, 3H), 3.15-3.00 (m, 2H)530.97 94.4 183 7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-10- (naphthalen-1-yl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, DMSO) δ 8.05 (t, J = 8.5 Hz, 2H), 7.72 (d, J = 4.5 Hz,1H), 7.68- 7.62 (m, 1H), 7.62-7.53 (m, 1H), 7.53-7.43 (m, 1H), 7.43-7.31 (m, 2H), 6.89-6.75 (m, 1H), 6.18 (dd, J = 16.6, 2.3 Hz, 1H),5.80-5.69 (m, 1H), 4.82-4.40 (m, 2H), 4.40- 4.08 (m, 2H), 4.08-3.38 (m,4H), 3.21-2.94 (m, 2H), 1.37-1.12 (m, 6H). 531.07 45.3 184 7-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1- yl)-9-chloro-10-(2,4-difluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1,1-dioxide

¹H NMR (400 MHz, DMSO) δ 8.21-8.03 (m, 1H), 7.49- 7.34 (m, 2H), 7.24(td, J = 8.5, 2.3 Hz, 1H), 6.89-6.71 (m, 1H), 6.17 (dd, J = 16.7, 2.2Hz, 1H), 5.74 (ddd, J = 10.4, 5.0, 2.2 Hz, 1H), 4.82-4.34 (m, 3H),4.27-3.97 (m, 2H), 3.96-3.48 (m, 5H), 1.41- 1.03 (m, 6H). 548.99 91.4189 7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.57-7.45 (m, 1H), 7.24- 7.15 (m, 1H),7.09-6.92 (m, 2H), 6.69-6.48 (m, 1H), 6.45- 6.28 (m, 1H), 5.82-5.72 (m,1H), 5.12-4.91 (m, 1H), 4.90-4.55 (m, 1H), 4.52- 4.19 (m, 2H), 4.20-3.96(m, 1H), 3.94-3.33 (m, 3H), 3.20- 3.01 (m, 2H), 1.53-1.18 (m, 6H).516.99 93.8 190 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1,1-dioxide

¹H NMR (400 MHz, DMSO) δ: 7.88 (s, 1H), 7.30-7.40 (m, 1H), 6.94-7.08 (m,2H), 6.49-6.19 (m, 1H), 6.39 (d, J = 16.8 Hz, 1H), 5.80 (d, J = 10.4 Hz,1H), 4.49-5.10 (m, 1H), 4.10-4.48 (m, 4H), 2.80- 4.10 (m, 6H), 1.39-1.50(m, 3H). 534.96 88.8 191 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1-oxide

¹H NMR (401 MHz, DMSO) δ: 7.89 (s, 1H), 7.11-7.20 (m, 1H), 7.03-7.10 (m,2H), 6.49-6.19 (m, 1H), 6.39 (d, J = 16.4 Hz, 1H), 5.80 (d, J = 10.4 Hz,1H), 4.38-5.20 (m, 3H), 3.30-4.30 (m, 6H), 2.78- 3.35 (m, 2H), 1.39-1.42(m, 3H). 518.96 26.6 192 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1-oxide

¹H NMR (401 MHz, DMSO) δ: 7.90 (s, 1H), 7.47-7.55 (m, 1H), 6.98-7.18 (m,2H), 6.49-6.19 (m, 1H), 6.39 (d, J = 16.4 Hz, 1H), 5.80 (d, J = 8.8 Hz,1H), 4.40-5.20 (m, 3H), 3.35-4.35 (m, 6H), 2.78- 3.33 (m, 2H), 1.39-1.41(m, 3H). 518.96 62.4 193 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (401 MHz, DMSO) δ: 7.48 (s, 1H), 7.16-7.23 (m, 1H), 6.95-7.08 (m,2H), 6.48-6.69 (m, 1H), 6.38 (d, J- 19.6 Hz, 1H), 5.78 (d, J = 10.0 Hz,1H), 4.95-4.45 (m, 3H), 4.34-3.98 (m, 3H), 3.80- 3.47 (m, 2H), 3.17-2.91(m, 3H), 1.39-1.38 (m, 3H). 502.96 97

Example 84:7-(9-acryloyl-3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-9-chloro-10-(2,4-difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

Over a solution of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(50 mg, 0.095 mmol) in dichloromethane (1 mL), triethylamine (54 mg,0.57 mmol) and acryloyl chloride (17 mg, 0.19 mmol) were added at 0° C.The reaction mixture was stirred at room temperature for two hours. Thesolvent was removed in vacuo to obtain a residue that was purified bypreparative HPLC to afford the desired product (9.2 mg, 15%) as anoff-white solid.

m/z (ESI, +ve)=579.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO) δ 7.95 (s, 1H), 7.52-7.44 (m, 1H), 7.41-7.38 (m,1H), 7.29-7.25 (m, 1H), 6.45-6.41 (m, 1H), 6.29-6.25 (m, 1H), 6.03 (d,J=12 Hz, 1H), 4.60-4.53 (m, 2H), 4.245-4.23 (m, 1H), 4.03-3.88 (m, 3H),3.65-3.55 (m, 2H), 3.52-3.47 (m, 1H), 3.23-3.05 (m, 3H), 2.73 (s, 2H)

Step 1: N,N-dibromobenzenesulfonamide

A solution of benzenesulfonamide (100 g, 0.6362 mol) and KOH (103 g,1.8357 mol) in water (700 mL) was stirred at room temperature for 30min. Bromine (91 mL, 1.7766 mol) was added dropwise and the mixturestirred for 16 hours. The reaction was filtered and the solid was washedwith water and dried under reduced pressure to affordN,N-dibromobenzenesulfonamide (240 g) as a yellow solid.

Step 2: diethyl 3,3′-((phenylsulfonyl)azanediyl)bis(2-bromopropanoate)

Ethyl prop-2-enoate (119.2 g, 1.19 mol) was added to a solution ofN,N-dibromobenzenesulfonamide (75 g, 0.24 mol) in dichloromethane (500mL) at room temperature. The mixture was stirred at 45° C. under lightfor 4 hours. Volatiles were removed under reduced pressure and the crudematerial purified by silica gel column chromatography (ethylacetate/hexanes=0-12%) to afford diethyl3,3′-((phenylsulfonyl)azanediyl)bis(2-bromopropanoate) as a white solid.

m/z (ESI, +ve)=515.9/517.9 (M+H)⁺.

Step 3:diethyl-1-benzyl-4-(phenylsulfonyl)piperazine-cis-2,6-dicarboxylate

To a solution of diethyl3,3′-((phenylsulfonyl)azanediyl)bis(2-bromopropanoate) (50 g, 0.0970mol) in toluene (150 mL) was added phenylmethanamine (52 g, 0.4853 mol).After stirring at 90° C. for 5 h, the mixture was cooled to roomtemperature and filtered. The filtrate was concentrated to afford aresidue that was purified by silica gel chromatography (ethylacetate/hexanes, 0-20%) to afford the desired product (26 g) as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ 7.78-7.74 (m, 2H), 7.65-7.60 (m, 1H),7.56-7.52 (m, 2H), 7.30-7.20 (m, 5H), 4.03 (q, J=7.2 Hz, 4H), 3.93 (s,2H), 3.42-3.38 (m, 2H), 3.36-3.31 (m, 2H), 3.18-3.13 (m, 2H), 1.23 (t,J=7.2 Hz, 6H).

Step 4: Cis-(1-benzyl-4-(phenylsulfonyl)piperazine-2,6-diyl)dimethanol

To a solution ofdiethyl-1-benzyl-4-(phenylsulfonyl)piperazine-cis-2,6-dicarboxylate (20g, 0.0434 mol) in THF (150 mL) was slowly added lithium aluminum hydride(5.8 g, 0.1528 mol) at 0° C. under nitrogen atmosphere. After stirringat 25° C. for 4 h, the mixture was quenched with water (6 mL) anddiluted with Na₂CO₃ (1 L). The mixture was extracted with ethyl acetate(500 mL×4). The combined organic layer was washed with brine (500 mL),dried over Na₂SO₄ and concentrated under reduced pressure. The residuewas dried by evaporation under reduced pressure to afford4-(benzenesulfonyl)-1-benzyl-cis-[2,6-(hydroxymethyl)piperazin-2-yl]methanol(32.8 g) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.78-7.75 (m, 2H), 7.66-7.61 (m, 1H),7.58-7.54 (m, 2H), 7.35-7.22 (m, 5H), 3.85 (s, 2H), 3.73-3.66 (m, 2H),3.61-3.55 (m, 2H), 3.28-3.22 (m, 2H), 2.95-2.90 (m, 4H), 2.03 (m, 2H).

Step 5:1-benzyl-cis-(2,6-bis(chloromethyl))-4-(phenylsulfonyl)piperazine

To a solution ofCis-(1-benzyl-4-(phenylsulfonyl)piperazine-2,6-diyl)dimethanol (32.8 g,0.0871 mol) in DMF (150 mL) was added thionyl chloride (32 mL, 0.4411)dropwise at 0° C. under nitrogen atmosphere. After stirring at roomtemperature for 4 hours, saturated aqueous sodium carbonate (900 mL) wasadded at 0° C. The mixture was extracted with ethyl acetate (500 mL×5)and the combined organic layers washed with water (500 mL×5), brine (500mL), dried over Na₂SO₄ and concentrated under reduced pressure to affordthe desired final product as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.81-7.78 (m, 2H), 7.65-7.62 (m, 1H),7.59-7.54 (m, 2H), 7.35-7.20 (m, 5H), 3.89 (s, 2H), 3.74-3.70 (m, 2H),3.58-3.54 (m, 2H), 3.49-3.43 (m, 2H), 3.05-3.01 (m, 2H), 2.67-2.62 (m,2H).

Step 6: 9-benzyl-7-(phenylsulfonyl)-3-thia-7,9-diazabicyclo[3.3.1]nonane

A mixture of1-benzyl-cis-(2,6-bis(chloromethyl))-4-(phenylsulfonyl)piperazine 0.01mol) and Na₂S (4.7 g, 0.06 mol) in EtOH (30 mL) was stirred at 80° C.for 16 hours. The mixture was cooled to room temperature, concentratedand the resulting residue was taken up in water (100 mL) and extractedwith ethyl acetate (50 mL×4). The combined organic layers were washedwith brine (50 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The crude material was purified by silica gel column (ethylacetate:hexanes=0-20%) to afford7-(benzenesulfonyl)-9-benzyl-3-thia-7,9-diazabicyclo[3.3.1]nonane (2.1g) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ7.82-7.79 (m, 2H), 7.62-7.53 (m, 3H), 7.29-7.23(m, 5H), 3.89 (s, 2H), 3.77-3.72 (m, 2H), 3.44-3.39 (m, 2H), 3.03-2.98(m, 4H), 2.30-2.26 (m, 2H).

Step 7:tert-butyl-9-benzyl-3-thia-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate

To a solution of9-benzyl-7-(phenylsulfonyl)-3-thia-7,9-diazabicyclo[3.3.1]nonane (500mg, 1.3 mmol) in THF (10 mL) was added KPPh₂ (0.5 M, 6.6 mL, 3.3 mmol)dropwise at −78° C. under nitrogen atmosphere. The solution was stirredat −78° C. for 3 hours and quenched with HCl (2 M, 5.2 mL, 10.4 mmol)followed by NaOH (2 M, 10.5 mL, 21 mmol). Boc anhydride (728 mg, 3.34mmol) was added and the mixture was stirred at room temperature for 16hours. The reaction was quenched with water (50 mL) and extracted withethyl acetate (30 mL×3). The combined organic layers were washed withbrine (30 mL) and concentrated to get a residue which was purified withpreparative thin layer chromatography (ethyl acetate:hexanes=1:4,Rf=0.5) to afford tert-butyl9-benzyl-3-thia-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (270 mg) asyellow solid.

¹H NMR (400 MHz, CDCl₃) δ 7.38-7.25 (m, 5H) 4.23-1.18 (m, 1H), 4.10-4.05(m, 1H), 3.95 (s, 2H), 3.48-3.32 (m, 4H), 2.88-2.83 (m, 2H), 2.31-2.26(m, 1H), 2.19-2.13 (m, 1H) 1.49 (s, 9H).

Step 8:tert-butyl-9-benzyl-3-thia-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate3,3-dioxide

To a solution oftert-butyl-9-benzyl-3-thia-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate(1 g, 3.0 mmol) in dichloromethane (20 ml) was added3-chloroperoxybenzoic acid (1.29 g, 7.5 mmol) at 0° C. The reactionmixture was stirred at room temperature for 30 minutes and quenched withsaturated Na₂S₂O₃ (50 mL) and extracted with dichloromethane (30 mL×3).The organic layers were combined, washed with brine (20 mL), dried oversodium sulphate and concentrated. The resulting residue was purified bysilica gel chromatography to affordtert-butyl-9-benzyl-3-thia-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate3,3-dioxide (0.9 g, 90%) as a light yellow solid.

m/z (ESI, +ve)=367.1 (M+H)⁺.

Step 9: tert-butyl-3-thia-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate3,3-dioxide

A solutiontert-butyl-9-benzyl-3-thia-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate3,3-dioxide (2.5 g, 0.27 mmol) Pd/Ba₂SO₄ (7.78 g) and HCl (5 drops) inmethanol (30 mL) was hydrogenated at room temperature for 2 hours. Themixture was filtered and concentrated to affordtert-butyl-3-thia-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate3,3-dioxide (1.3 g, 72%) as a white solid after purification by flashchromatography.

m/z (ESI, +ve)=277.1 (M+H)⁺.

Step 10: 3-thia-7,9-diazabicyclo[3.3.1]nonane 3,3-dioxide

A solution oftert-butyl-3-thia-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate3,3-dioxide

(1.2 g) in dichloromethane/trifluoroacetic acid (5/1, 20 mL) was stirredat room temperature for 4 hours. The solution was concentrated and theresulting residue purified by reversed phase chromatography to afford3-thia-7,9-diazabicyclo[3.3.1]nonane 3,3-dioxide (620 mg) as a whitesolid.

m/z (ESI, +ve)=177.1 (M+H)⁺.

Step 11: methyl 2-amino-4-bromobenzoate

A solution of 2-amino-4-bromobenzoic acid (100 g, 0.4628 mol) in thionylchloride (400 mL) was stirred at 80° C. for 2 hours. The mixture wascooled to room temperature and concentrated under reduced pressure. Theresidue was dissolved in dichloromethane (500 mL) and cooled down to 0°C. Methanol (200 ml) was added and the mixture stirred at 0° C. for 1hour. After that time, the reaction was quenched with saturated aqueousNaHCO₃ (400 mL) and extracted with dichloromethane (300 mL×3). Thecombined organic layers were washed with brine (300 mL), dried oversodium sulphate and concentrated to afford methyl2-amino-4-bromobenzoate (100 g, 80%) as a yellowish green solid.

m/z (ESI, +ve)=230.0 (M+H)⁺.

Step 12: methyl 2-acetamido-4-bromobenzoate

To a solution of methyl 2-amino-4-bromobenzoate (60 g, 0.26 mol) inacetic acid (300 mL) at room temperature, was added acetic anhydride(26.6 g, 0.2608 mol). The mixture was stirred at 100° C. for 2 hours andcooled down to room temperature. Water was added (400 mL) and theresulting suspension was filtered to afford methyl2-acetamido-4-bromobenzoate (58 g) as a yellow solid.

m/z (ESI, +ve)=272.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO) δ 10.63 (s, 1H), 8.53 (s, 1H), 7.83 (d, J=8.0 Hz,1H), 7.39 (dd, J=8.0, 2.0, 1H), 3.86 (s, 3H), 2.15 (s, 3H).

Step 13: methyl 2-acetamido-4-bromo-5-chlorobenzoate

To a solution of methyl 2-acetamido-4-bromobenzoate (58 g, 0.21 mol) inDMF (250 mL), was added N-chlorosuccinimide (28.48 g, 0.21 mol) at roomtemperature. The mixture was stirred at 85° C. for 16 hours, dilutedwith water (250 mL) and extracted with ethyl acetate (250 mL×3). Thecombined organic layers were washed with brine (200 mL×4), dried overNa₂SO₄, filtered and concentrated to give a yellow oil which waspurified by flash chromatography with ethyl acetate in hexanes(50-100%). The resulting material was dissolved in DMF (250 mL) andN-chlorosuccinimide (14.2 g, 0.1067 mol) was added. The mixture wasstirred at 85° C. for 3 hours and quenched with water (250 mL). Thesolution was extracted with ethyl acetate (250 mL×3) and the combinedorganic layers were washed with brine (200 mL×4), dried over Na₂SO₄,filtered and concentrated to afford a residue that was purified bysilica gel chromatography (ethyl acetate:hexanes=0-55%) to afford methyl2-acetamido-4-bromo-5-chlorobenzoate (47 g, 72%) as a yellow solid.

m/z (ESI, +ve)=305.9 (M+H)⁺.

Step 14: methyl 2-amino-4-bromo-5-chlorobenzoate

Methyl 4-bromo-5-chloro-2-acetamidobenzoate (47 g, 0.15 mol) wasdissolved in a methanolic solution of HCl (5M, 500 mL) and the mixturestirred at 80° C. for 2 hours. The reaction was diluted with water (500mL) and filtered to afford methyl 2-amino-4-bromo-5-chlorobenzoate(crude, 39 g, 90%) as a white solid.

m/z (ESI, +ve)=263.9 (M+H)⁺.

Step 15: methyl5-amino-2-chloro-2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylate

To a mixture of methyl 2-amino-4-bromo-5-chlorobenzoate (39 g, 0.15 mol)in dioxane/H₂O (240 mL) were added (2,4-difluorophenyl)boronic acid(23.69 g, 0.15 mol), 1,1′-bis(diphenylphosphino)ferrocene palladiumdichloride (21.95 g, 0.03 mol) and Cs₂CO₃ (146.62 g, 0.45 mol). Themixture was stirred at 100° C. for 10 hours, quenched with H₂O (200 mL)and extracted with ethyl acetate (100 mL×3). The combined organic layerswere washed with brine (200 mL), dried over sodium sulphate andconcentrated to afford a crude material that was purified by silica gelchromatography to afford methyl5-amino-2-chloro-2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylate (27.1 g,61%) as a yellow solid.

m/z (ESI, +ve)=298.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO) δ 7.78 (s, 1H), 7.47-7.36 (m, 2H), 7.23-7.18 (m,1H), 6.85 (s, 2H), 6.82 (s, 1H), 3.83 (s, 3H).

Step 16: methyl3-amino-6-chloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate

To a solution of methyl5-amino-2-chloro-2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylate (27.1 g,90.9 mmol) in AcOH (240 mL) was added N-iodosuccinamide (22.4 g, 99.5mmol). The mixture was stirred at room temperature for 2 hours. Thevolatiles were removed under reduced pressure and the resulting residuewas dissolved in ethyl acetate (30 mL) and washed with saturated aqueousNa₂S₂O₃ (20 mL×3), brine (20 mL×3), dried with Na₂SO₄ and filtered. Thefiltrate was concentrated and the crude material triturated in ethylacetate (15 mL). The solid was collected by filtration and dried toafford methyl3-amino-6-chloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate(22.1 g, 57%) as an off-white solid.

¹H NMR (400 MHz, DMSO) δ 7.92 (s, 1H), 7.46-7.40 (m, 1H), 7.34-7.22 (m,2H), 6.92 (s, 2H), 3.87 (s, 3H).

Step 17:3-amino-6-chloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylic acid

To a solution of methyl3-amino-6-chloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate(22.1 g, 52.1 mmol) in THF/methanol/water (75/75/35 mL) was added NaOH(21 g, 0.525 mol). The mixture was stirred at room temperature for 16hours. The organic solvents were removed and the residue was acidifiedto pH=4-5 by addition of 5 M HCl and extracted with ethyl acetate (300mL×3). The combined organic layers were washed with brine (200 mL),dried over Na₂SO₄ and concentrated to afford3-amino-6-chloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylic acid(20 g, 99%) as a yellow solid.

¹H NMR (400 MHz, DMSO) δ 7.92 (s, 1H), 7.43-7.19 (m, 5H).

Step 18:6-chloro-7-(2,4-difluorophenyl)-8-iodoquinazoline-2,4(1H,3H)-dione

A mixture of3-amino-6-chloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylic acid(20 g, 48.8 mmol) and urea (350 g, 5.8 mol) was stirred at 200° C. for 2hours. The solid was taken up in ethyl acetate (4×500 mL) and washedwith water (500 mL) and brine (300 mL). The organic layer was dried overNa₂SO₄, concentrated and the residue purified by silica gelchromatography (dichloromethane:methanol=9:1) to afford6-chloro-7-(2,4-difluorophenyl)-8-iodoquinazoline-2,4(1H,3H)-dione (14g, 66%) as a white solid.

¹H NMR (400 MHz, DMSO) δ 11.77 (s, 1H), 9.60 (s, 1H), 8.04 (s, 1H),7.51-7.45 (m, 1H), 7.32-7.22 (m, 2H), 6.79 (s, 2H).

Step 19:6-chloro-7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)quinazoline-2,4(1H,3H)-dione

To a mixture of6-chloro-7-(2,4-difluorophenyl)-8-iodoquinazoline-2,4(1H,3H)-dione (5 g,11.5 mmol), CuI (437 mg, 2.3 mmol) and K₂CO₃ (4.8 g, 34.8 mmol) inisopropyl alcohol:ethylene glycol (100 mL:50 mL) was added2-mercaptoethan-1-ol (3 mL, 38.5 mmol) at room temperature. The mixturewas stirred at 90° C. for 16 hours. The reaction mixture wasconcentrated and the residue purified by reversed phase chromatographyto afford6-chloro-7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)quinazoline-2,4(1H,3H)-dione(3.2 g, 72%) as a white solid.

¹H NMR (400 MHz, DMSO) δ 11.73 (s, 1H), 10.33 (s, 1H), 8.06 (s, 1H),7.45-7.38 (m, 2H), 7.28-7.22 (m, 1H), 5.37 (t, J=4.8 Hz, 1H), 3.38-3.36(m, 2H), 2.65-2.61 (m, 2H).

Step 20:9-chloro-10-(2,4-difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dione

To a solution of triphenylphosphine (4.6 g, 17.7 mmol) in THF (50 mL)was added DIAD (3.6 g, 17.7 mmol) at 0° C. under nitrogen atmosphere andthe mixture stirred at 0° C. for 20 minutes.6-chloro-7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)quinazoline-2,4(1H,3H)-dione(3.4 g, 8.83 mmol) was added and the reaction mixture was stirred atroom temperature for 16 hours. The mixture was concentrated and thecrude material purified by reversed phase chromatography to afford9-chloro-10-(2,4-difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dione(1.6 g, 49%) as a white solid.

m/z (ESI, +ve)=367.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (s, 1H), 7.86 (s, 1H), 7.51-7.46 (m,1H), 7.41-7.35 (m, 1H), 7.30-7.25 (m, 1H), 4.39-4.33 (m, 1H), 4.10-4.03(m, 1H), 3.20-3.10 (m, 2H).

Step 21:9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

To a solution of9-chloro-10-(2,4-difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dione(300 mg, 0.82 mmol) in toluene (5 mL) were addedN,N-diisopropylethylamine (634 mg, 4.9 mmol) and POCl₃ (5 mL). Thereaction mixture was stirred at 120° C. for 1.5 hours. The reactionmixture was concentrated and the residue redissolved in dichloroethane(5 mL) and added slowly over a solution of3-thia-7,9-diazabicyclo[3.3.1]nonane 3,3-dioxide (577 mg, 3.27 mmol) andN,N-diisopropylethylamine (634 mg, 4.9 mmol) in dichloroethane (5 mL) at0° C. The reaction mixture was stirred at room temperature for 1 hour,concentrated and the crude residue purified by preparative thin layerchromatography to afford9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(150 mg, 34%) as a yellow solid.

m/z (ESI, +ve)=525.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO) δ 8.76-8.71 (m, 1H), 7.94-7.89 (m, 1H), 7.50-7.45(m, 1H), 7.41-7.38 (m, 1H), 7.29-7.25 (m, 1H), 4.53-4.40 (m, 1H),4.26-4.21 (m, 1H), 4.18-4.05 (m, 1H), 4.00-3.90 (m, 2H), 3.62-3.48 (m,5H), 3.24-3.08 (m, 4H), 3.00-2.85 (m, 1H).

Example 100:7-(4-acryloyl-6,6-dioxidohexahydrothieno[3,4-b]pyrazin-1(2H)-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

The title compound was prepared analogously to Example 84 where10-(2,4-difluorophenyl)-7-(6,6-dioxidohexahydrothieno[3,4-b]pyrazin-1(2H)-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.

m/z (ESI, +ve)=613.0 (M+H)⁺.

Step 1: methyl 3-amino-2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylate

A solution of methyl 2-amino-4-bromobenzoate (11 g, 0.0478 mol)(2,4-difluorophenyl)boronic acid (8.3 g, 0.052 mol),1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (7.0 g, 0.0095mol) and Cs₂CO₃ (46.7 g, 0.1434 mol) in dioxane:H₂O (4:1, 220 mL) wasstirred at 100° C. for 16 hours. The reaction was cooled to roomtemperature, diluted with water (100 mL) and extracted with ethylacetate (3×100 mL). The organic layers were combined and washed withbrine (200 mL), dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel chromatography to afford methyl3-amino-2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylate (11 g, 86%) as alight yellow solid.

m/z (ESI, +ve)=264.1 (M+H)⁺.

Step 2: methyl5-amino-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate

A solution of methyl3-amino-2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylate (11.7 g, 0.044 mol)and N-iodosuccinimide (10 g, 0.044 mmol) in DMF (100 mL) was stirred atroom temperature for 16 hours. The solution was diluted with water (500mL) and extracted with ethyl acetate (3×100 mL). The organic layer waswashed with brine (300 mL), dried over Na₂SO₄ and concentrated to yielda residue that was purified by silica gel chromatography affordingmethyl 5-amino-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate (15.4g, 89%) as a yellow solid.

m/z (ESI, +ve)=390.0 (M+H)⁺.

Step 3: methyl5-acetamido-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate

To a solution of methyl 2-amino-4-(2,4-difluorophenyl)-5-iodobenzoate(22 g, 0.0565 mol) in AcOH (40 mL) was added acetic anhydride (5.77 g,0.0565 mol), the mixture was stirred at 100° C. for 2 h. The mixture wasquenched with water (1000 mL) and filtered, the filter cake wascollected and dried under reduced pressure to afford methyl5-acetamido-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate (5.26 g,70%) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ10.54 (s, 1H), 8.36 (s, 1H), 8.19 (s, 1H),7.46-7.41 (m, 2H), 7.25-7.20 (m, 1H), 3.93 (s, 3H), 2.18 (s, 3H).

Step 4: methyl5-acetamido-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate

A solution of methyl 4-(2,4-difluorophenyl)-2-acetamido-5-iodobenzoate(8.7 mg, 20.2 mmol), copper(I) iodide (5.4 g, 28.4 mmol) andtetrabutylammonium iodide (3.7 g, 10.0 mmol) in HMPA (60 mL) was stirredat 90° C. for 20 minutes. Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate(29 g, 151.0 mmol) was added and the resulting mixture stirred at 90° C.for 16 hours. The solution was cooled to room temperature, diluted withwater (150 mL), extracted with ethyl acetate (3×150 mL) and the organiclayers washed with brine (100 mL), dried over Na₂SO₄ and concentrated toafford a residue which was purified by silica gel chromatography (ethylacetate:hexanes=0-25%).5-acetamido-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylatewas isolated as a yellow solid in 70% yield.

¹H NMR (400 MHz, DMSO-d6) δ10.81 (s, 1H), 8.33 (s, 1H), 8.26 (s, 1H),7.46-7.41 (m, 2H), 7.25-7.20 (m, 1H), 3.93 (s, 3H), 2.18 (s, 3H).

Step 5: methyl5-amino-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate

A solution of methyl5-acetamido-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate(5.26 g, 14.1 mmol) in a methanolic solution of HCl (100 mL) was stirredat 80° C. for 2 hours and concentrated to afford a residue that wasdissolved in ethyl acetate (500 mL) and washed with water (2×100 mL).The organic layer was washed with brine (150 mL), dried over Na₂SO₄ andconcentrated to afford methyl5-amino-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate(5.2 g) as brown oil.

m/z (ESI, +ve)=332.0 (M+H)⁺.

Step 6: methyl3-amino-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate

To a solution of methyl5-amino-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate(5.3 g, 16 mmol) in AcOH (35 mL) was added N-iodosuccinamide (3.4 g, 15mmol) and stirred at 25° C. for 16 h. The solution was concentrated, theresidue dissolved in ethyl acetate (400 mL) and washed withNa₂S₂O₃/NaHCO₃ (3×100 mL), brine (100 mL), dried over Na₂SO₄ andconcentrated to afford methyl3-amino-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate(5 g) as a yellow solid.

m/z (ESI, +ve)=457.9 (M+H)⁺.

Step 7:3-amino-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylicacid

To a mixture of methyl3-amino-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate(10 g, 21.8 mmol) in THF (24 mL), methanol (16 mL) and water (16 mL) wasadded NaOH (8.72 g, 218 mmol). The reaction mixture was stirred at roomtemperature for 2 hours. The mixture was concentrated under reducedpressure to afford a residue. 1 M HCl was added over this crude materialand the pH adjusted to 5-6, extracted with EtOAc (20 mL/3). The organicphases were combined, washed with brine (10 mL), dried over Na₂SO₄ andfiltered. The filtrate was concentrated under reduced pressure to affordthe3-amino-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylicacid (9 g, 89%) as a pink solid.

m/z (ESI, +ve)=442.94 (M+H)⁺.

Step 8:7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

3-amino-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylicacid (13 g, 29.34 mmol) was added to urea (105.64 g, 1760.4 mmol). Thereaction mixture was stirred at 100° C. for 2 h. The mixture was cooledto 100° C., water (500 mL) was added and stirred for 30 min, filteredand the filter cake was washed with EtOAc (1400 mL). The filtrate wascollected and concentrated under reduced pressure to afford a solid thatwas washed with methanol (100 mL) to afford7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(5.8 g, 42%) as a yellow solid.

m/z (ESI, +ve)=467.94 (M+H)⁺.

Step 9:7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

To a solution of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(5.8 g, 0.0124 mol), Cuprous iodide (470 mg, 0.0024 mol) and Potassiumcarbonate (5.14 g, 00.0372 mol) in isopropyl alcohol (30 ml) andethylene glycol (60 ml) was added 2-mercaptoethan-1-ol (2.91 g, 0.0372mol). The reaction mixture was stirred at 85° C. for 36 hours. Themixture was concentrated under reduced pressure and the crude materialpurified by reverse column chromatography (phase A: water (0.10% TFA),phase B: CAN, 0˜41%) to afford7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(2.1 g, 39%) as a white solid.

m/z (ESI, +ve)=418.04 (M+H)⁺.

Step 10:10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dione

To a solution of Triphenylphosphine (1.69 g, 6.4 mmol) in THF (10 ml)cooled to 0° C. was added N,N-Diisopropylethylamine (1.30 g, 6.4 mmol)and stirred for 30 minutes.7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(1.8 g, 6.4 mmol) was added and stirred at 0° C. for 1 hour. The mixturewas concentrated under reduced pressure and the residue purified byreverse column chromatography (phase A: water (0.1% TFA), phase B: ACN;0˜50%) to afford10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dione(1.4 g, 77%) as a white solid.

m/z (ESI, +ve)=400.03 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ12.03 (s, 1H), 8.10 (s, 1H), 7.52-7.45 (m,1H), 7.38-7.32 (m, 1H), 7.29-7.18 (m, 1H), 4.34-4.32 (m, 1H), 4.16-4.07(m, 1H), 3.23-3.10 (m, 2H).

Step 11: diethyl pyrazine-2,3-dicarboxylate

To a solution of pyrazine-2,3-dicarboxylic acid (15 g, 0.03 mol) in EtOH(100 mL) was added thionyl chloride (10 mL) at 0° C. The mixture wasstirred at 80° C. for 2 h. The solvent was removed to afford a residuethat was purified by silica gel chromatography to afford diethylpyrazine-2,3-dicarboxylate (18.5 g, 92%) as a light-yellow oil.

m/z (ESI, +ve)=225.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO) δ 8.96 (s, 2H), 4.40 (d, J=8.0 Hz, 4H), 1.33 (t,J=8.0 Hz, 6H).

Step 12: syn-(diethyl-piperazine-2,3-dicarboxylate)

A mixture of diethyl pyrazine-2,3-dicarboxylate (13.8 g, 0.062 mol) and10% palladium on carbon (2.4 g) in EtOH (50 ml) was stirred underhydrogen at 50 psi for 20 h. The suspension was filtered through a padof celite and the filter cake was washed with EtOH. The filtrate wasconcentrated under reduced pressure to afford diethyl(2S,3R)-piperazine-2,3-dicarboxylate (13.8 g, 97%) as a brown oil.

m/z (ESI, +ve)=231.2 (M+H)⁺.

Step 13: diethyl-1,4-dibenzylpiperazine-cis-2,3-dicarboxylate

To a solution of cis-(diethyl-piperazine-2,3-dicarboxylate) (13.8 g,0.06 mol) in ACN (60 mL) were added (bromomethyl)benzene (20.5 g, 0.12mol) and potassium carbonate (24.9 g, 0.18 mol). The mixture was stirredat room temperature for 16 h. The solvent was removed, the residue wassuspended in H₂O (100 mL) and extracted with ethyl acetate (50 mL×3).The combined organic layers were washed with brine (50 mL), dried oversodium sulphate and concentrated in vacuo to afford a residue that waspurified by silica gel chromatography to afford the desired product(14.8 g, 56%) as a light yellow oil.

m/z (ESI, +ve)=411.2 (M+H)⁺.

¹H NMR (400 MHz, DMSO) δ 7.34-7.23 (m, 10H), 4.21-4.00 (m, 4H),3.83-3.78 (m, 2H), 3.49 (s, 2H), 3.44-3.41 (m, 2H), 3.00-2.98 (m, 2H),2.27-2.23 (m, 2H), 1.19 (t, J=8.0 Hz, 6H).

Step 14: (1,4-dibenzylpiperazine-cis-2,3-diyl)dimethanol

To a solution of diethyl-1,4-dibenzylpiperazine-cis-2,3-dicarboxylate(14.8 g, 0.036 mol) in THF (100 mL) was added LiAlH₄ (2.73 g, 0.072mmol) at 0° C. The mixture was stirred at room temperature for 5 h andthen quenched with 10% NaOH and extracted with ethyl acetate (30 mL×3).The combined organic layers were washed with brine (50 mL), dried oversodium sulphate and concentrated under reduced pressure to afford(1,4-dibenzylpiperazine-cis-2,3-diyl)dimethanol) (11.5 g, 97%) as ayellow solid.

m/z (ESI, +ve)=327.2 (M+H)⁺.

¹H NMR (400 MHz, DMSO) δ 7.32-7.26 (m, 8H), 7.31-7.19 (m, 2H), 4.69 (t,J=4.0 Hz, 2H), 3.96-3.92 (m, 2H), 3.81-3.76 (m, 2H), 3.66-3.63 (m, 2H),3.44-3.41 (m, 2H), 2.74-2.73 (m, 2H), 2.55-2.51 (m, 2H), 2.23-2.18 (m,2H).

Step 15: 1,4-dibenzylpiperazine-cis-2,3-diyl-bis(methylene)dimethanesulfonate

To a solution of (1,4-dibenzylpiperazine-cis-2,3-diyl)dimethanol (3.26g, 10 mmol) in dichloromethane (30 mL) at 0° C. was added Et₃N (3.03 g,30 mmol), followed by MsCl (2.85 g, 25 mmol). The reaction mixture wasstirred at 0° C. for 2 hours. Upon completion, the mixture was washedwith brine (20 mL) three times. The organic layers were dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to afford1,4-dibenzylpiperazine-cis-2,3-diyl-bis(methylene) dimethanesulfonate(3.6 g, 75%) which was used directly in the next step.

Step 16: 1,4-dibenzyl-cis-octahydrothieno[3,4-b]pyrazine

To a solution of 1,4-dibenzylpiperazine-cis-2,3-diyl-bis(methylene)dimethanesulfonate

(3.6 g, 7.5 mmol) in EtOH (30 mL) was added Na₂S (2.9 g, 37.5 mmol). Themixture was stirred at 80° C. for 16 hours, cooled down to roomtemperature and concentrated. The residue was diluted with water (30 mL)and extracted with EtOAc (30 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄ and concentrated to afford a residue thatwas purified by column chromatography yielding the desired product aslight yellow oil (1.8 g, 75%).

m/z (ESI, +ve)=325.0 (M+H)⁺.

Step 17: cis-octahydrothieno[3,4-b]pyrazine

To a solution of 1,4-dibenzyl-cis-octahydrothieno[3,4-b]pyrazine (1 g,3.1 mmol) in dichloroethane (10 mL) was added 1-chloroethylchloroformate (4.43 g, 31 mmol). The reaction mixture was stirred at 80°C. for 16 hours, cooled down to room temperature and concentrated. Theresidue was dissolved in methanol (10 ml) and stirred at 80° C. for 4hours. The resulting suspension was filtered and the filter cake waswashed with methanol and dried to afford the desired product (0.44 g,92%) as a white solid.

m/z (ESI, +ve)=145.2 (M+H)⁺.

Step 18: dibenzyl-cis-hexahydrothieno[3,4-b]pyrazine-1,4-dicarboxylate

To a solution of cis-octahydrothieno[3,4-b]pyrazine (440 mg, 3.05 mmol)in dioxane/water (20 mL) at 0° C., benzyl chloroformate (1.1 g, 6.71mmol) and NaHCO₃ (366 mg, 9.15 mmol) were added. The reaction mixturewas stirred at room temperature for 16 hours. The solvent was removed,H₂O (20 mL) was added and the mixture extracted with ethyl acetate (20mL×3). The organic layers were combined, washed with brine (50 mL),dried over sodium sulphate and concentrated in vacuo to afford a residuethat was purified by silica gel chromatography to afforddibenzyl-cis-hexahydrothieno[3,4-b]pyrazine-1,4-dicarboxylate (870 mg,69%) as colorless oil.

m/z (ESI, +ve)=413.2 (M+H)⁺.

Step 19: dibenzyl-cis-hexahydrothieno[3,4-b]pyrazine-1,4-dicarboxylate6,6-dioxide

To a solution ofdibenzyl-cis-hexahydrothieno[3,4-b]pyrazine-1,4-dicarboxylate (840 mg,2.04 mmol) in dichloromethane (10 mL) at 0° C., was added3-chloroperoxybenzoic acid (880 mg, 5.1 mmol). and the reaction mixturewas stirred at room temperature for 4 hours. The reaction was quenchedwith H₂O (20 mL) and extracted with dichloromethane (10 mL×3). Thecombined organic layers were washed with brine (20 mL), dried oversodium sulphate and concentrated to afford a residue that was purifiedby silica gel chromatography to afforddibenzyl-cis-hexahydrothieno[3,4-b]pyrazine-1,4-dicarboxylate6,6-dioxide (920 mg, 91%) as a white solid.

m/z (ESI, +ve)=467.1 (M+Na)⁺.

Step 20: cis-octahydrothieno[3,4-b]pyrazine 6,6-dioxide

To a solution ofdibenzyl-cis-hexahydrothieno[3,4-b]pyrazine-1,4-dicarboxylate6,6-dioxide (760 mg, 1.71 mmol) in acetic acid (20 ml) was addedbromhidric acid (6 ml). The reaction mixture was stirred at 50° C. for20 hours. The suspension was filtered, the solid washed with ethylacetate and dried to afford cis-octahydrothieno[3,4-b]pyrazine6,6-dioxide (340 mg, 74%) as a white solid.

m/z (ESI, +ve)=177.1 (M+H)⁺.

¹H NMR (400 MHz, D₂O) δ 4.43 (d, J=5.0 Hz, 2H), 3.70-3.66 (m, 4H),3.38-3.28 (m, 4H).

Step 21:10-(2,4-difluorophenyl)-7-(6,6-dioxidohexahydrothieno[3,4-b]pyrazin-1(2H)-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

To a solution of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dione(70 mg, 0.05 mmol) in toluene (1 mL) were addedN,N-diisopropylethylamine (135 mg, 1.0 mmol) and POCl₃ (1 mL). Thereaction mixture was stirred at 120° C. for 1.5 hours, cooled down toroom temperature and concentrated to afford a residue that was dissolvedin dichloroethane (1 mL) and added to a solution ofoctahydrothieno[3,4-b]pyrazine 6,6-dioxide (118 mg, 0.35 mmol) andN,N-diisopropylethylamine (135 mg, 1.0 mmol) in dichloroethane (1 mL).The reaction mixture was stirred at room temperature for 1 hour,concentrated and the resulting solid purified by silica gelchromatography to afford10-(2,4-difluorophenyl)-7-(6,6-dioxidohexahydrothieno[3,4-b]pyrazin-1(2H)-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(50 mg, 51%) as a yellow solid.

m/z (ESI, +ve)=559.1 (M+H)⁺.

Example Pyrimidone-Thiomorpholines-B

12. Syntheses of Intermediates for Substituted Tricyclic ThiomorpholineCompounds

6-chloro-7-(2,4-difluorophenyl)-8-iodoquinazoline-2,4(1H,3H)-dione

5-amino-2-chloro-2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylic acid (2)

To a mixture of 2-amino-4-bromo-5-chlorobenzoic acid (20 g, 79.7 mmol),(2,4-difluorophenyl)boronic acid (37.8 g, 239.1 mmol) and K₂CO₃ (33 g,239.1 mmol) in dioxane/H₂O (200 mL/40 mL) was added Xphos-Pd-G2 (4.7 g,5.6 mmol). The reaction mixture was stirred at 80° C. under nitrogenatmosphere for 6 hours. The mixture was filtrated and diluted with H₂O.The pH was adjusted to 2 with 2N HCl, then extracted with EtOAc. Theorganic layer was washed with brine and then concentrated in vacuo. Thesolid obtained was washed with ACN to give5-amino-2-chloro-2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylic acid (7.6g+17 g crude) as an off white solid.

LC-MS: m/z 284.2 [M+H]⁺

3-amino-6-chloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylic acid(3)

To a mixture of5-amino-2-chloro-2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylic acid (21.6g, 76.3 mmol) in AcOH (250 mL) was added NIS (25.7 g, 114.4 mmol) at 0°C. The reaction mixture was stirred at rt overnight. The reactionmixture was concentrated in vacuum and diluted with H₂O. The reactionwas quenched by Na₂S₂O₃ (aq), then extracted with EtOAc (200 mL). Theorganic phase was washed with brine (150 mL), concentrated in vacuum togive the crude product3-amino-6-chloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylic acid(26 g crude) as brown solid.

LC-MS: m/z 409.9 [M+H]⁺.

6-chloro-7-(2,4-difluorophenyl)-8-iodoquinazoline-2,4(1H,3H)-dione (4)

To a 250 mL glass pressure vessel equipped with stirring bar was charged3-amino-6-chloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylic acid(26 g, 63.56 mmol) and urea (38 g, 635.6 mol). The vessel was placed ona preheated block at 200° C. and the reaction was stirred for 4 h. Themixture reaction mixture was cooled to 80° C. and diluted with water.After filtration, the filter cake was washed with Petroleum Ether/EtOAc(30 mL/10 mL) to give6-chloro-7-(2,4-difluorophenyl)-8-iodoquinazoline-2,4(1H,3H)-dione (7.6g, yield: 27%) as a white solid.

LC-MS: m/z 433.1[M−H]⁺.

5-((tert-butyldiphenylsilyl)oxy)-1-mercaptopentan-2-ol

tert-butyl(pent-4-en-1-yloxy)diphenylsilane (2)

To a solution of pent-4-en-1-ol (25 g, 290 mmol) and imidazole (29 g,435 mmol) in DMF (400 mL) was added TBDPSCl (95 g, 348 mmol) at 0° C.The mixture was stirred at rt for 16 hours. The mixture was concentratedto remove most of DMF followed by the addition of H₂O (500 mL. Theresulting mixture was extracted with EtOAc (500 mL×3). The organiclayers were combined and concentrated under reduced pressure. Theresidue was purified by silica gel column with 1% EA in PE to afford theproduct (74 g, 79%) as light yellow oil. MS (ESI) m/z 325.2 [M+H]⁺.

5-((tert-butyldiphenylsilyl)oxy)pentane-1,2-diol (3)

To a solution of tert-butyl(pent-4-en-1-yloxy)diphenylsilane (58 g, 179mmol) in t-BuOH (300 mL) and H₂O (300 mL) was added AD-mix-α (232 g) at0° C. The mixture was stirred at rt for 16 hours. The reaction wasquenched with NaS₂O₃ aqueous solution and stirred at rt for 2 h. Thenthe mixture was extracted with EtOAc (500 mL×3). The organic layer wasconcentrated, and the residue was purified by silica gel column with 5%MeOH in DCM to afford the product (55 g, 85%) as light yellow oil. MS(ESI) m/z 359.2 [M+H]⁺.

5-((tert-butyldiphenylsilyl)oxy)-2-hydroxypentyl4-methylbenzenesulfonate (4)

To a solution of 5-((tert-butyldiphenylsilyl)oxy)pentane-1,2-diol (54 g,152 mmol) and TEA (43 mL, 304 mmol) in DCM (500 mL) was added TsCl (32g, 167 mmol) at 0° C. The mixture was stirred at rt for 16 hours. 500 mLof H₂O was added and extracted with DCM (500 mL×3). The organic layerwas concentrated, and the residue was purified by silica gel column with10% EtOAc in PE to afford the product (50 g, 64%) as light yellow oil.MS (ESI) m/z 513.2 [M+H]⁺.

5-((tert-butyldiphenylsilyl)oxy)-1-mercaptopentan-2-ol (5)

To a solution of 5-((tert-butyldiphenylsilyl)oxy)-2-hydroxypentyl4-methylbenzenesulfonate (44 g, 87 mmol) in the dry DMF (120 mL) wasadded NaSH (14 g, 260 mmol). The mixture was stirred at rt for 1 h. 500mL H₂O was added and extracted with EtOAc (400 mL×3). The organic layerwas concentrated, and the residue was purified by silica gel column with8% EtOAc in Petroleum Ether to afford the product (22 g, 67%) as lightyellow oil. MS (ESI) m/z 375.1 [M+H]⁺.

7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

methyl 2-acetamido-4-chloro-5-iodobenzoate (2)

To a mixture of methyl 2-amino-4-chloro-5-iodobenzoate (50.00 g, 160.51mmol) in AcOH (500 mL) was added Ac₂O (19.66 g, 192.61 mmol). Themixture was stirred at 100° C. for 16 hours. After completion, themixture was cooled to rt, filtered and washed with Petroleum Ether (200mL) to afford crude product (35 g, yield: 62%) as white solid. MS (ESI)m/z 353.9 [M+H]⁺.

Methyl 2-acetamido-4-chloro-5-(trifluoromethyl)benzoate (3)

To a mixture of methyl 2-acetamido-4-chloro-5-iodobenzoate (35.00 g,98.98 mmol) in DMF (350 mL) was added methyl2,2-difluoro-2-(fluorosulfonyl)acetate (70.09 g, 395.99 mmol), HMPA(70.98 g, 395.99 mmol) and CuI (15.05 g, 79.19 mmol). The mixture wasstirred at 90° C. under N₂ for 16 hours. After completion, the mixturewas poured into water (300 mL), extracted with EtOAc (200 mL×3). Thecombined organic phases were washed with brine (500 mL) and dried overNa₂SO₄, After filtration and concentration, the residue was purified bysilica gel column with Petroleum Ether/EtOAc=100/1 to 20/1 to afforddesired product (25.00 g, yield: 84%) as white solid. MS (ESI) m/z 296.0[M+H]⁺.

Methyl5-acetamido-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate(4)

To a mixture of methyl 2-acetamido-4-chloro-5-(trifluoromethyl)benzoate(20.00 g, 98.98 mmol) in dioxane (200 mL) and water (20 mL) was added(2,4-difluorophenyl)boronic acid (35.02 g, 202.95 mmol), Pd(dppf)Cl₂(7.42 g, 10.14 mmol) and K₃PO₄ (43.08 g, 202.95 mmol). The mixture wasstirred at 85° C. under N₂ for 2 h. (2,4-difluorophenyl)boronic acid(35.02 g, 202.95 mmol) was added to above solution, then the mixture wasstirred at 85° C. under N₂ for 16 hours. After completion, the mixturewas poured into water (200 mL), extracted with EtOAc (150 mL×3). Thecombined organic phases were washed with brine (300 mL) and dried overNa₂SO₄, After filtration and concentration, the residue was purified bysilica gel column using a gradient of Petroleum Ether/EtOAc (50/1 to15/1) to afford the desired product (16.60 g, yield: 62%) as whitesolid. MS (ESI) m/z 374.0 [M+H]⁺

Methyl5-amino-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate(5)

A mixture of methyl5-acetamido-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate(26.00 g, 69.65 mmol) in HCl/MeOH (300 mL) was stirred at 70° C. for 2h. The mixture was concentrated and a saturated aqueous solution ofNaHCO₃ (100 mL) was added. The resulting mixture was extracted withEtOAc (50 mL×3). The combined organic phases were combined, washed withbrine (100 mL) and dried over Na₂SO₄. The solvent was removed in vacuoto afford the crude product (23.00 g) as a yellow solid. MS (ESI) m/z332.0 [M+H]⁺

Methyl3-amino-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate(6)

To a mixture of methyl5-amino-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate(23.00 g, 69.44 mmol) in AcOH (200 mL) was added NIS (18.75 g, 83.32mmol). The mixture was stirred at 50° C. for 2 h. After completion, themixture was poured into water (200 mL), extracted with EtOAc (150 mL×3).The combined organic phases were washed with brine (300 mL) and driedover Na₂SO₄. After filtration and concentration, the residue waspurified by silica gel column with Petroleum Ether/EtOAc=200/1 to 20/1to afford the desired product (26.00 g, 62% yield) as white solid. MS(ESI) m/z 457.9 [M+H]⁺

7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(7)

To a solution of methyl methyl3-amino-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate(25.00 g, 54.69 mmol) in dioxane (200 mL) and water (200 mL) was addedNaOH (4.37 g, 109.38 mmol). The mixture was stirred at 90° C. for 3 h.After completion, the mixture was poured into water (200 mL). AdjustedpH=4˜5 and extracted with EtOAc (150 mL×3). The combined organic phaseswere washed with brine (300 mL) and dried over Na₂SO₄. The solvent wasremoved in vacuo to give3-amino-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylicacid (24 g, crude) as yellow solid.

A mixture of3-amino-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylicacid (5.00 g, 11.28 mmol) and urea (13.55 g, 225.68 mmol) was stirred at198° C. for 6 hours. After completion, the mixture was cooled to 80° C.,water (200 mL) was added to the solution and stirred for 1 h. Themixture was filtrated to afford the desired product (3.00 g, 56% yield)as a white solid. MS (ESI) m/z 467.9 [M+H]⁺

(R)-benzyl 4-(2-hydroxy-3-mercaptopropyl)piperidine-1-carboxylate

(S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (2)

To a mixture of (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (50 g, 378mmol), DMAP (6.0 g, 49 mmol) and TEA (105 mL, 755 mmol) in DCM (500 mL)was added TsCl (108.2 g, 567.5 mmol) at 0° C. The mixture was stirred atrt overnight. The reaction solution was poured into NaHCO₃ (aq) (1.2 L)and stirred for 1 h. The mixture was extracted with DCM (200 mL). Theorganic layer was washed with water (1 L), dried over Na₂SO₄, filteredand concentrated under reduced pressure to afford the title compound(119.3 g, crude) as a colorless oil, which was used to next step withoutfurther purification. MS (ESI) m/z 287.1 [M+H]⁺.

(S)-4-(iodomethyl)-2,2-dimethyl-1,3-dioxolane (3)

To a mixture of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl4-methylbenzenesulfonate (119.3 g, 378.3 mmol) in acetone (900 mL) wasadded NaI (1.12 kg, 7.57 mol). The mixture was stirred at 75° C.overnight. The reaction solution was filtered and the solvent wasremoved in vacuo. The residue was redissolved with EtOAc (1 L) and theresulting solution was washed with water (1.5 L), Na₂SO₃ (aq, 500 mL)and brine (500 mL). The water phase was extracted with EtOAc (1 L). Thecombined organic phases were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (10% ethyl acetate in petroleum ether) to afford thetitle compound (81.4 g, 1.08 mmol, 83% yield) as yellow liquid. ¹H NMR(400 MHz, CDCl₃) δ 4.31-4.25 (m, 1H), 4.17-4.13 (m, 1H), 3.80-3.77 (m,1H), 3.27-3.24 (m, 1H), 3.14 (t, J=8.8 Hz, 1H), 1.46 (s, 3H), 1.35 (s,3H).

(R)-tert-butyl4-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5,6-dihydropyridine-1(2H)-carboxylate(4)

To a mixture of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(54 g, 174.8 mmol) in dioxane (550 ml) was added Ni(dme)Br₂ (5.4 g, 17.5mmol), Cy-DMEDA (2.48 g, 17.5 mmol) and t-BuOK (39.2 g, 349.6 mmol) at0° C. under N₂. The mixture was heated to 60° C. for 18 hours and wasdiluted with H₂O and extracted with EtOAc. The organic layer was washedwith water and brine. The solvent was removed in vacuo, and the residuewas purified by column with a mixture of Petroleum Ether/EtOAc (10:1) toafford (R)-tert-butyl4-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5,6-dihydropyridine-1(2H)-carboxylate(29.5 g, 57% yield) as a yellow oil; LC-MS: m/z 198.1. [M+H-Boc]⁺.

(R)-tert-butyl4-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)piperidine-1-carboxylate (5)

To a mixture of (R)-tert-butyl4-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5,6-dihydropyridine-1(2H)-carboxylate(29.5 g, 99.3 mol) in MeOH (300 mL) was added Pd/C (7 g). The mixturewas stirred at rt under H₂ for 4 h. The reaction was determined to becompleted by LCMS and the mixture was filtered. The filtrate wasconcentrated under reduced pressure to afford (R)-tert-butyl4-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)piperidine-1-carboxylate (22g, crude) as yellow oil; LC-MS: m/z 200.2 [M+H-Boc]⁺.

(R)-3-(piperidin-4-yl)propane-1,2-diol (6)

To a mixture of (R)-tert-butyl4-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)piperidine-1-carboxylate (22g, 73.6 mmol) in DCM (40 ml) at rt was added TFA (40 mL). Then themixture was stirred at rt for 2 h. After completion, the pH was adjustedto 7-8 with NH₃.H₂O. The mixture was concentrated to afford crudecompound 6 (R)-3-(piperidin-4-yl)propane-1,2-diol (13 g, crude) as paleyellow oil; LC-MS: m/z 160.1. [M+H]⁺.

(R)-benzyl 4-(2,3-dihydroxypropyl)piperidine-1-carboxylate (7)

To a mixture of (R)-3-(piperidin-4-yl)propane-1,2-diol (12 g, 75.5 mol)and Na₂CO₃ (24 g, 226.5 mmol) in THF (90 mL) and H₂O (90 mL) was addedCbzCl (19.3 g, 113.2 mol) slowly at 0° C. Then the mixture was stirredat 0° C. for 3 h. The mixture was extracted with EA (500 mL), theorganic phase was washed with brine (300 mL). The solvent was removed invacuo, and the residue was purified by silica gel column with a mixtureof DCM/MeOH (30/1) to afford the title (R)-benzyl4-(2,3-dihydroxypropyl)piperidine-1-carboxylate (15 g, 68% yield) ascolorless oil. LC-MS: m/z 294.1 [M+H]⁺.

(R)-benzyl 4-(2-hydroxy-3-mercaptopropyl)piperidine-1-carboxylate (8)

To a solution of (R)-benzyl4-(2,3-dihydroxypropyl)piperidine-1-carboxylate (15 g, 51.13 mmol) andTEA (10.3 g, 102.26 mmol) in DCM (150 mL) was added TsCl (8.77 g, 46.02mmol) at 0° C. The mixture was stirred at rt for 4 hours and H₂O (500mL) was added. The reaction mixture was extracted with DCM (500 mL×3).The solvent was removed in vacuo, and the residue was purified by silicagel column with a mixture of DCM/MeOH (20/1) to afford the title product(13.6 g, 59%) as light yellow oil. MS (ESI) m/z 448.1 [M+H]⁺.

(R)-benzyl 4-(2-hydroxy-3-mercaptopropyl)piperidine-1-carboxylate (9)

To a solution of (R)-benzyl4-(2-hydroxy-3-mercaptopropyl)piperidine-1-carboxylate (13.6 g, 30.42mmol) in the dry DMF (50 mL) was added NaSH (5.1 g, 91.28 mmol), themixture was stirred at rt under N₂ for 1 hour. H₂O (200 mL) was addedand the resulting mixture was extracted with EA (200 mL×3). The solventwas removed in vacuo, and the residue was purified by silica gel columnusing a mixture of PE/EA (2/1) to afford the desired product (5.3 g,56%) as light yellow oil. MS (ESI) m/z 310.1 [M+H]⁺.

(R)-benzyl 4-(3-hydroxy-2-mercaptopropyl)piperazine-1-carboxylate

(R)-benzyl 4-(oxiran-2-ylmethyl)piperazine-1-carboxylate (2)

To a solution of (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (25 g,96.52 mmol) in ACN (150 mL) was added benzyl piperazine-1-carboxylate(19.3 g, 75.75 mmol) and K₂CO₃ (24 g, 175.5 mmol) at 0° C. undernitrogen atmosphere. The mixture was stirred at room temperature for 22hours. After completion, the solvent was removed in vacuo, and theresidue was purified by silica gel column with a mixture of DCM/MeOH(50:1) to afford the desired crude product (24.5 g) as a light yellowoil. LC-MS: m/z 277.4 [M+H]⁺.

(R)-benzyl 4-(3-hydroxy-2-mercaptopropyl)piperazine-1-carboxylate (3)

To a mixture of (R)-benzyl 4-(oxiran-2-ylmethyl)piperazine-1-carboxylate(24.5 g, 88.7 mmol) and triphenylphosphine (17.4 g, 97.5 mmol) in THF(250 mL) was slowly added TBAF (26.7 mL, 26.7 mmol, 1M in THF) at 0° C.under nitrogen atmosphere. The mixture was stirred at room temperaturefor 1 h. After completion, the solvent was removed in vacuo, and theresidue was purified by silica gel column with a gradient ofDCM/MeOH=100:1-80:1 to afford the title product (20.8 g, 67 mmol, yield:76%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.31 (m, 5H),5.13 (s, 2H), 3.80-3.78 (m, 1H), 3.54-3.50 (m, 4H), 3.39 (s, 1H),2.66-2.57 (m, 4H), 2.46-2.40 (m, 4H), 1.57-1.52 (m, 1H); LC-MS: m/z311.5 [M+H]⁺.

6-chloro-7-(2,4,6-trifluorophenyl)-8-iodoquinazoline-2,4(1H,3H)-dione

methyl 5-amino-2-chloro-2′,4′,6′-trifluoro-[1,1′-biphenyl]-4-carboxylate(2)

To a mixture of methyl2-amino-5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(11.00 g, 35.4 mmol) in THF (50 mL) and water (10 mL) was added2-bromo-1,3,5-trifluorobenzene (22.39 g, 106.1 mmol), Xphos-Pd-G₂ (2.78mg, 3.54 mmol) and K₃PO₄ (22.49 g, 106.1 mmol). The reaction mixture wasstirred at 55° C. under N₂ for 15 h, After completion, the solvent wasremoved in vacuo, and the residue was purified by silica gel column witha gradient of Petroleum Ether/EtOAc (20/1 to 2/1) to afford the desiredproduct (10.8 g, 95% yield) as yellow solid. MS (ESI) m/z 316.0 [M+H]⁺

methyl3-amino-6-chloro-2′,4′,6′-trifluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate(3)

To a mixture of methyl5-amino-2-chloro-2′,4′,6′-trifluoro-[1,1′-biphenyl]-4-carboxylate (10.8g, 34.18 mmol) in acetic acid (50 mL) was added NIS (11.54 g, 51.27mmol). The mixture was stirred at 30° C. for 12 h. After completion, themixture was concentrated and the residue was poured into sat.NaHCO₃ (100mL), extracted with EtOAc (50 mL×3). The combined organic phases werewashed with brine (100 mL), dried over Na₂SO₄, and concentrated to givethe crude product (7.36 g, crude) as yellow solid.

3-amino-6-chloro-2′,4′,6′-trifluoro-2-iodo-[1,1′-biphenyl]-4-carboxylicacid (4)

To a mixture of methyl3-amino-6-chloro-2′,4′,6′-trifluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate(7.36 g, 16.70) in methanol (100 mL) and water (10 mL) was added NaOH(2.67 g, 66.76 mmol). The mixture was stirred at 70° C. for 3 h. Aftercompletion, the mixture was poured into water (200 mL), the pH wasadjusted to 4˜5 and the mixture was extracted with EtOAc (50 mL×3). Thecombined organic phases was washed with brine (50 mL), dried overNa₂SO₄, and concentrated to give the product (4.56 g, 46% yield) asyellow solid. MS (ESI) m/z 427.9 [M+H]⁺

6-chloro-8-iodo-7-(2,4,6-trifluorophenyl)quinazoline-2,4(1H,3H)-dione(5)

A mixture of3-amino-6-chloro-2′,4′,6′-trifluoro-2-iodo-[1,1′-biphenyl]-4-carboxylicacid (4.56 g, 10.67 mmol) and urea (12.81 g, 213.58 mmol) was stirred at180° C. for 6 h. After completion, the mixture was cooled to 80° C.Water (200 mL) was added to the mixture and stirred for 1 hour. Themixture was filtrated to give desired product (2.4 g, yield: 51%) aspale yellow solid. MS (ESI) m/z 452.9 [M+H]⁺

Syntheses of Substituted Tricyclic Thiomorpholine Compounds B. Example99(3R)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-3-methyl-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

(S)-2-hydroxypropyl 4-methylbenzenesulfonate (2)

To a mixture of (S)-propane-1,2-diol (3.5 g, 46 mmol) and TEA (7.7 mL,55.2 mmol) in DCM (30 mL) was added TsCl (8.78 g, 46 mmol) at 0° C. Themixture was stirred at rt for 2 hours. The solvent was evaporated andthe residue was purified by silica gel chromatography (500% ethylacetate in petroleum ether) to afford the title compound (3.0 g, 13mmol, 28% yield) as colorless oil. MS (ESI) m/z 230.28 [M+H]⁺.

(S)-1-mercaptopropan-2-ol (3)

To a mixture of (S)-2-hydroxypropyl 4-methylbenzenesulfonate (1.5 g, 6.5mmol) in EtOH (10 mL) was added NaHS (1.1 g, 19.5 mmol). The mixture wasstirred at 50° C. for 0.5 h. The solvent was removed in vacuo, and theresidue was diluted with DCM. The filtrate was concentrated under reducepressure to give the title compound (599 mg, 6.5 mmol, crude) ascolorless oil.

6-chloro-7-(2,4-difluorophenyl)-8-(((S)-2-hydroxypropyl)thio)quinazoline-2,4(1H,3H)-dione(4)

The mixture of6-chloro-7-(2,4-difluorophenyl)-8-iodoquinazoline-2,4(1H,3H)-dione (1.5g, 3.45 mmol), CuI (262 mg, 1.38 mmol), (S)-1-mercaptopropan-2-ol (599mg, 3.45 mmol) and K₂CO₃ (1.43 g, 10.3 mmol) in iso-Propyl alcohol andethylene glycol (15 mL, v/v=2:1) was stirred under nitrogen atmosphereat 85° C. for 5 hours. After completion, the mixture was concentratedand the residue was purified by silica gel column with a gradient ofDCM/MeOH (50:1-30:1) to afford the desired product (311 mg, 0.78 mmol,22% yield) as a light yellow solid. LC-MS: m/z 398.9 [M−H]⁺.

(3R)-9-chloro-10-(2,4-difluorophenyl)-3-methyl-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(5)

To a mixture of6-chloro-7-(2,4-difluorophenyl)-8-(((S)-2-hydroxypropyl)thio)quinazoline-2,4(1H,3H)-dione(321 mg, 0.8 mmol) and triphenylphosphine (1.26 g, 4.83 mmol) in THF (50mL) was slowly added DEAD (842 mg, 4.83 mmol) at 0° C. under nitrogenatmosphere. The mixture was stirred at room temperature for 1 hour. DCM(50 mL) was added. The organic phase was washed with water (50 mL×2) anddried over Na₂SO₄. The solvent was removed in vacuo, and the residue waspurified by silica gel column with a mixture of Petroleum Ether/EtOAc(0-50%) to afford the title product (100 mg, 0.26 mmol, 32% yield) as ayellow solid. LC-MS: m/z 380.9 [M−H]⁺.

(3S)-tert-butyl4-((3R)-9-chloro-10-(2,4-difluorophenyl)-3-methyl-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(6)

To a solution of(3R)-9-chloro-10-(2,4-difluorophenyl)-3-methyl-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione (100 mg, 0.26 mmol) and K₂CO₃ (181 mg, 1.31mmol), DMAP (4 mg, 0.02 mmol) in ACN (2 mL) was added Ts₂O (128 mg, 0.39mmol). The mixture was stirred at rt for 5 hours. Then (S)-tert-butyl3-methylpiperazine-1-carboxylate (117 mg, 0.41 mmol) and TEA (0.1 mL,0.78 mmol) was added to above mixture and stirred at rt for 2 h. Aftercompletion, the mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column with a gradient of PE/EA(20%-80%) to afford desired product (72 mg, yield: 49%) as yellow solid.LC-MS: m/z 563.0 [M+H]⁺;

(3R)-9-chloro-10-(2,4-difluorophenyl)-3-methyl-7-((S)-2-methylpiperazin-1-yl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(7)

To a solution of (3S)-tert-butyl4-((3R)-9-chloro-10-(2,4-difluorophenyl)-3-methyl-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(72 mg, 0.12 mmol) in dichloromethane (2 mL) was added TFA (0.7 mL) at0° C. The mixture was stirred at rt for 1 hour and concentrated to givethe crude product (72 mg, crude) as yellow solid. LC-MS: m/z 463.0[M+H]⁺;

(3R)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-3-methyl-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a mixture of(3R)-9-chloro-10-(2,4-difluorophenyl)-3-methyl-7-((S)-2-methylpiperazin-1-yl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(72 mg, 0.12 mmol) and triethyl amine (65 mg, 0.64 mmol) indichloromethane (3 mL) was added acrylic anhydride (32 mg, 0.25 mmol) at0° C. The mixture was stirred at rt for 1 hour. The solvent was removedin vacuo, and the residue was purified by prep-HPLC to afford thedesired product (25 mg, 38% yield) as yellow solid. LC-MS: m/z 517.1[M+H]⁺.

C. Example 341(3R)-3-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propyl)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

(S)-7-bromo-8-((5-((tert-butyldiphenylsilyl)oxy)-2-hydroxypentyl)thio)-6-chloroquinazoline-2,4(1H,3H)-dione(2)

To a mixture of 7-bromo-6-chloro-8-iodoquinazoline-2,4(1H,3H)-dione (572mg, 1.42 mmol), Xantphos (123 mg, 0.21 mmol), K₂CO₃ (392 mg, 2.84 mmol)in dioxane (10 mL) was added5-((tert-butyldiphenylsilyl)oxy)-1-mercaptopentan-2-ol (800 mg, 2.14mmol) and Pd₂(dba)₃ (128 mg, 0.14 mmol) at rt. The reaction mixture wasstirred at 50° C. under nitrogen atmosphere for 22 hours. After removingthe solvent, the residue was purified by silica gel columnchromatography (dichloromethane/methanol=100/1 to 50/1) to affordcompound (2)(S)-7-bromo-8-((5-((tert-butyldiphenylsilyl)oxy)-2-hydroxypentyl)thio)-6-chloroquinazoline-2,4(1H,3H)-dione(510 mg, yield: 55%) as a light yellow solid.

LC-MS: m/z 647.6 [M−H]⁺

(R)-10-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)propyl)-9-chloro-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(3)

To a mixture of(S)-7-bromo-8-((5-((tert-butyldiphenylsilyl)oxy)-2-hydroxypentyl)thio)-6-chloroquinazoline-2,4(1H,3H)-dione(1.0 g, 1.51 mmol) and triphenylphosphine (587.1 mg, 2.25 mmol) in THF(10 mL) was added DEAD (411.7 mg, 2.25 mmol) slowly at 0° C. undernitrogen atmosphere. The mixture was stirred at room temperature for 1hour. The organic phase was washed with water (50 mL×2), dried overNa₂SO₄(S) and concentrated. The residue was purified by silica gelcolumn with a gradient of PE/EA=0-50% to afford the product (788.1 mg,1.25 mmol, yield: 83%) as a yellow solid. LC-MS: m/z=630.1 [M−H]⁺.

(S)-tert-butyl4-((R)-10-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)propyl)-9-chloro-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(4)

To a solution of(R)-10-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)propyl)-9-chloro-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(1.68 mg, 2.67 mmol) and K₂CO₃ (1.84 g, 13.35 mmol) in ACN (20 mL) wasadded TPSCl (1.2 g, 4.05 mmol), the mixture was stirred at rt for 5 h.After the reaction was completed, (S)-tert-butyl3-methylpiperazine-1-carboxylate (1.60 g, 8.01 mmol) was added. Theresulting mixture was stirred at rt for 2 hours. After completion, themixture was concentrated under reduced pressure and the residue waspurified by silica gel column with a gradient of DCM/MeOH (30:1-20:1) toafford desired product (610 mg, 28% yield) as yellow solid. MS (ESI) m/z813.2 [M+H]⁺.

(S)-tert-butyl4-((R)-10-bromo-9-chloro-3-(3-hydroxypropyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(5)

To a solution of (S)-tert-butyl4-((R)-10-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)propyl)-9-chloro-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(610 mg, 0.75 mmol) in THF (5 mL) was added TBAF (1 mL, 1M in THF). Themixture was stirred at 20° C. for 2 hours. The reaction mixture waspoured into water (50 mL) and extracted with EtOAc (20 mL×3). Thecombined organic phases were washed with brine (10 mL), dried overNa₂SO₄, and concentrated. The residue was purificatied by silica gelcolumn with as gradient of DCM/MeOH (30:1-20:1) to give the product (320mg, 0.56 mmol) as yellow solid. LC-MS: m/z 575.1 [M+H]⁺

(S)-tert-butyl4-((R)-10-bromo-9-chloro-5-oxo-3-(3-oxopropyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(6)

To a solution of4-((R)-10-bromo-9-chloro-3-(3-hydroxypropyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(5) (290 mg, 0.5 mmol) in DCM (5 mL) was added Dess-martin reagent (318mg, 0.75 mmol). The mixture was stirred at 20° C. under nitrogenatmosphere for 2 hours. After removing the solvent, the residue waspurified by silica gel column chromatography(dichloromethane/methanol=30/1) to give the product (275 mg, 96% yield)as yellow solid. LC-MS: m/z 573.1 [M+H]⁺

(S)-tert-butyl4-((R)-3-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propyl)-10-bromo-9-chloro-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(7)

To a solution of (S)-tert-butyl4-((R)-10-bromo-9-chloro-5-oxo-3-(3-oxopropyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(275 mg, 0.50 mmol) and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (150mg, 1.5 mmol) in DCM was added sodium cyanoborohydride (150 mg, 0.75mmol). The mixture was stirred at 20° C. for 2 hours. After removing thesolvent, the residue was purified by silica gel column chromatography(dichloromethane/methanol=20/1) to give the desired product (300 mg, 90%yield) as yellow solid. LC-MS: m/z 656.2 [M+H]⁺

(3S)-tert-butyl4-((3R)-3-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propyl)-9-chloro-10-(2,4-difluorophenyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(8)

A mixture of (S)-tert-butyl4-((R)-3-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propyl)-10-bromo-9-chloro-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(140 mg, 0.21 mmol), (2,4-difluorophenyl)boronic acid (160 mg, 1.05mmol), Pd(dppf)Cl₂ (15 mg, 0.02 mmol) and K₃PO₄ (125 mg, 0.63 mmol) indioxane (5 mL) and H₂O (0.8 mL) was heated to 85° C. under nitrogenatmosphere for 3 hours. The mixture was concentrated, and the residuewas purified by silica gel column chromatography(dichloromethane/methanol=30/1) to give the crude product (130 mg,crude) as brown solid. LC-MS: m/z 688.2 [M+H]⁺

(3R)-3-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propyl)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9)

The mixture of (3S)-tert-butyl4-((3R)-3-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propyl)-9-chloro-10-(2,4-difluorophenyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(130 mg, 0.19 mmol) in DCM/TFA (3 mL/1 mL) was stirred at 20° C. for 1hour. Removing solvent in vacuo gave the crude product as the TFA salt(160 mg, crude).

To the mixture of above product (160 mg, crude) and triethyl amine (57mg, 0.57 mmol) in dichloromethane (3 mL) was added acrylic anhydride(47.8 mg, 0.38 mmol) slowly at 0° C. The mixture was stirred for 1 hour.After removing solvent in vacuo, the residue was purified by prep-HPLCto afford the desired product (60 mg, 50% yield) as white solid. LC-MS:m/z 642.2 [M+H]⁺.

D. Example 767-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-2,2-dimethyl-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

6-chloro-7-(2,4-difluorophenyl)-8-((1-hydroxy-2-methylpropan-2-yl)thio)quinazoline-2,4(1H,3H)-dione(2)

Compound 1 (50 mg, 0.123 mmol, 1 equiv) and2-mercapto-2-methylpropan-1-ol (26 mg, 0.246 mmol, 2 equiv) was added toa 5 mL microwave vial and dissolved in 2-isopropyl alcohol (0.5 mL) andethylene glycol (0.25 mL). Next, the solution was degassed with N₂ for30 min and CuI (9.4 mg, 0.049 mmol, 0.4 equiv) and K₂CO₃ (53 mg, 0.381mmol, 3 equiv) were added followed by additional degassing with N₂ for20 min. The microwave vial was fitted with a crimp-top cap and placed ona heated block at 90° C. The resulting reaction mixture was heterogenousand light tan in color. After 33 hours, the vial was removed from theheating block, allowed to cool, and the solvent was removed underreduced pressure. This was performed in two separate batches (50 mg,each) and combined. The combined crude material was suspended in CH₂Cl₂and filtered. The filtrate was collected, and the solvent was removed byrotary evaporation. The crude material was purified by flash columnchromatography using an Isolera One Biotage instrument (0-4%MeOH/CH₂Cl₂, 10 g column, 0% (5 CV), 0-4% (20 CV), 4% (5 CV)) to providea brown oil (45 mg) containing unknown impurities, but used in thesubsequent step: TLC (3% MeOH/CH₂Cl₂) R_(f)=0.17; ¹H NMR (400 MHz,CDCl₃) δ 8.27 (dd, J=8.8 Hz, 1H), 7.14-6.91 (m, 3H), 4.01-3.82 (m, 2H),3.51-3.30 (m, 2H), 1.34 (s, 3H), 1.30 (s, 3H); LRMS-ESI (m/z) [M+H]⁺calculated for C₁₈H₁₆ClF₂N₂O₃S 413.05, found 413.1.

9-chloro-10-(2,4-difluorophenyl)-2,2-dimethyl-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dione(3)

Compound 2 (20 mg, 0.048 mmol, 1 equiv) and PPh₃ (19 mg, 0.073 mmol, 1.5equiv) was added to a 10 mL round-bottom flask under a N₂ atmosphere anddissolved in CH₂Cl₂ (1 mL, 0.05 M). A solution of DCAD (27 mg, 0.073mmol, 1.5 equiv) in CH₂Cl₂ (0.73 mL, 0.5 M) was added dropwise to thereaction mixture at room temperature. After 1 h, the reaction reached31% conversion determined by LC-MS. Additional DCAD (27 mg, 0.073 mmol,1.5 equiv) and PPh₃ (19 mg, 0.073 mmol, 1.5 equiv) was added to thereaction mixture and after 15 min the reaction reached full conversionby LC-MS. The reaction mixture was diluted with CH₂Cl₂ (ca. 50 mL) andthe precipitate filtered. The filtrate was collected, and the solventwas removed by rotary evaporation. The crude material was purified bypreparative thin-layer chromatography (Silica Gel 60 F₂₅₄, 0.5 mm) using3% MeOH/CH₂Cl₂ to provide compound 3 (13 mg, 68%) as a white solid: TLC(3% MeOH/CH₂Cl₂) R_(f)=0.51; ¹H NMR (400 MHz, MeOH-d₄) δ 7.98 (s, 1H),7.18-7.04 (m, 3H), 4.24 (d, J=13.4 Hz, 1H), 3.98 (d, J=13.4 Hz, 1H),1.40 (s, 3H), 1.37 (s, 3H); LRMS-ESI (m/z) [M−H]⁻ calculated forC₁₈H₁₂ClF₂N₂O₂S 393.03, found 393.0.

tert-Butyl(3S)-4-(9-chloro-10-(2,4-difluorophenyl)-2,2-dimethyl-5-oxo-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(4)

Compound 3 (13 mg, 0.033 mmol, 1 equiv) was dissolved in MeCN (0.4 mL,0.1 M) under a N₂ atmosphere in a 1 dr vial. K₂CO₃ (13.7 mg, 0.099 mmol,3 equiv) was added to the reaction mixture and the reaction mixture wasbriefly sonicated. p-Toluenesulfonic anhydride (22 mg, 0.066 mmol, 2equiv) was added to the reaction mixture at room temperature. Thereaction mixture was stirred for 14 h and reached near full conversiondetermined by LC-MS. Next, tert-butyl(S)-3-methylpiperazine-1-carboxylate (13.2 mg, 0.066 mmol, 2 equiv) andK₂CO₃ (13.2 mg, 0.066 mmol, 2 equiv) was added to the vial and stirredfor 15 min at room temperature. The intermediate was determined to befully consumed by LC-MS and the solvent was removed by under reducedpressure. The mixture was transferred with CH₂Cl₂ to a separatoryfunnel, washed with aqueous saturated NH₄Cl (10 mL) and H₂O (10 mL),extracted with CH₂Cl₂ (2×50 mL), dried over Na₂SO₄, and filtered. Thesolvent was removed by rotary evaporation to afford compound 4 (26 mg)as a yellow oil which contained starting material (˜47%; determined byLC-MS) in addition to other minor unknown impurities. This material wasused as is in the subsequent step: TLC (3% MeOH/CH₂Cl₂) R_(f)=0.32;LRMS-ESI (m/z) [M+H]⁺ calculated for C₂₈H₃₂ClF₂N₄O₃S 577.19, found577.2.

7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-2,2-dimethyl-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(5)

Compound 4 (26 mg crude, 0.045 mmol, 1 equiv) was dissolved in anhydrousCH₂Cl₂ (3 mL) in a 20 dr vial followed by the addition of CF₃COOH (1 mL)at room temperature and capped. After 15 min, the reaction wasdetermined to be complete by LC-MS and the solvent was removed by rotaryevaporation. The reaction mixture was dissolved in MeOH, loaded onto aHyperSep SCX plug, and flushed with MeOH (ca. 20 mL). Next, the desiredintermediate was eluted with 1N NH₃ in MeOH (ca. 20 mL) and collected.The solvent was removed by rotary evaporation and the crude material wasdissolved in anhydrous CH₂Cl₂ (3 mL) in a 20 dr vial and capped. Next,DIPEA (8 μL, 0.045 mmol, 1 equiv) was added by syringe to the reactionat room temperature followed by acryloyl chloride (3.6 μL, 0.045 mmol, 1equiv) and capped. After 15 min, the reaction was determined to becomplete by LC-MS and the solvent was removed by rotary evaporation. Thecrude material was dissolved in MeOH, filtered with a 0.45 μm PTFE plug,and purified by preparative RP-HPLC (Luna 5 μM C18(2) 100 Å, 100×30 mm,5-95% MeCN+0.1% (v/v) HCOOH and H₂O+0.1% (v/v) HCOOH). The productfractions were collected, and the solvent was removed by rotaryevaporation, followed by lyophilization (−91 to −71° C.; <0.01 mbar) indeionized water to afford compound 5 (1.46 mg) as a white solid: ¹H NMR(400 MHz, MeOH-d₄) δ 7.71 (d, J=4.5 Hz, 1H), 7.33-7.22 (m, 1H),7.18-7.09 (m, 2H), 6.91-6.73 (m, 1H), 6.29 (dd, J=16.2. 7.2 Hz, 1H),5.81 (dd, J=10.6. 1.9 Hz, 1H), 4.68-3.93 (m, 5H), 3.80-3.45 (m, 2H),1.42 (s, 3H), 1.38 (s, 3H); LRMS-ESI (m/z) [M+H]⁺ calculated forC₂₆H₂₆ClF₂N₄O₂S 531.14, found 531.2.

E. Example 350(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(2,4-difluorophenyl)-3-((4-ethylpiperazin-1-yl)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

benzyl4-((2R)-3-((7-(2,4-difluorophenyl)-4-hydroxy-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-8-yl)thio)-2-hydroxypropyl)piperazine-1-carboxylate(2)

The mixture of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(2.3 g, 4.91 mmol), (R)-benzyl4-(2-hydroxy-3-mercaptopropyl)piperazine-1-carboxylate (2.28 g, 7.38mmol), CuI (750 mg, 3.93 mmol) and K₂CO₃ (2.03 g, 14.73 mmol) inethane-1,2-diol (30 mL) and i-PrOH (30 mL) was stirred under nitrogenatmosphere at 85° C. for 22 hours. After removing solvent in vacuo, theresidue was purified by silica gel column using DCM/MeOH=50:1 as eluentto afford the title product (1.2 g, 1.84 mmol, 37% yield) as a lightyellow solid. MS (ESI) m/z 651.5 [M+H]⁺.

benzyl4-(((3S)-10-(2,4-difluorophenyl)-7-hydroxy-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperazine-1-carboxylate(3)

To a mixture of benzyl4-((2R)-3-((7-(2,4-difluorophenyl)-4-hydroxy-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-8-yl)thio)-2-hydroxypropyl)piperazine-1-carboxylate(1.2 g, 1.84 mmol) and triphenylphosphine (964 mmol, 3.68 mmol) in THF(30 mL) was added DEAD (640 mg, 3.68 mmol) slowly at 0° C. undernitrogen atmosphere. The mixture was stirred at room temperature for 1h. DCM (50 mL) was added. The organic phase was washed with water (50mL×2), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by silica gel column with a gradient of PE/EA (10:1-5:1 toafford the desired product (710 mg, 1.12 mmol, 61% yield) as a lightyellow solid. MS (ESI) m/z 633.6 [M+H]⁺.

(3S)-tert-butyl4-((3S)-3-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(4)

To a mixture of benzyl4-(((3S)-10-(2,4-difluorophenyl)-7-hydroxy-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperazine-1-carboxylate(710 mg, 1.20 mmol) and K₂CO₃ (497 mg, 3.61 mmol) in ACN (20 mL) wasadded TPSCl (543 mg, 1.8 mmol). The mixture was stirred at rt for 5 h.After the reaction was completed, (S)-tert-butyl3-methylpiperazine-1-carboxylate (720 mg, 3.6 mmol) and TEA (370 mg, 3.6mmol) was added. The resulting mixture was stirred at rt for 2 hours.The reaction mixture was concentrated under reduced pressure and theresidue was purified by silica gel column with a gradient of PE/EA(20%-80%) to afford desired product (720 mg, yield: 68%) as yellowsolid. MS (ESI) m/z 815.3 [M+H]⁺.

(3S)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-5-oxo-3-(piperazin-1-ylmethyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(5)

The mixture of benzyl4-(((3S)-10-(2,4-difluorophenyl)-7-hydroxy-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperazine-1-carboxylate(640 mg, 0.78 mmol) and Pd/C (500 mg) in methanol was stirred underhydrogen atmosphere for 3 hours. After filtration, the solvent wasremoved in vacuo. The residue was purification by silica gel column witha gradient of DCM/MeOH (5%-10%) to afford desired product (410 mg, 77%yield) as yellow solid. MS (ESI) m/z 680.2 [M+H]⁺.

(3S)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-3-((4-ethylpiperazin-1-yl)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(6)

To a mixture of (3S)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-5-oxo-3-(piperazin-1-ylmethyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate (150 mg, 0.22 mmol)and acetaldehyde (0.5 mL, 40% in water) in EtOH was added sodiumtriacetoxyborohydride (88 mg, 0.44 mmol). The mixture was stirred at 20°C. for 2 hours. After removing solvent in vacuo, the residue waspurified by silica gel column chromatography(dichloromethane/methanol=30/1) to give the product (118 mg, 75% yield)as yellow solid. MS (ESI) m/z 709.2 [M+H]⁺

(3S)-10-(2,4-difluorophenyl)-3-((4-ethylpiperazin-1-yl)methyl)-7-((S)-2-methylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(7)

To a solution of (3S)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-3-((4-ethylpiperazin-1-yl)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(110 mg, 0.16 mmol) in DCM (3 mL) was added TFA (0.8 mL). The mixturewas stirred at 20° C. for 2 hours. The mixture was concentrated to givethe crude product as the TFA salt which was used in next step withoutfurther purification.

(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(2,4-difluorophenyl)-3-((4-ethylpiperazin-1-yl)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a mixture of(3S)-10-(2,4-difluorophenyl)-3-((4-ethylpiperazin-1-yl)methyl)-7-((S)-2-methylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(80 mg, 0.13 mmol) and triethyl amine (41 mg, 0.40 mmol) in DCM (3 mL)was added acrylic anhydride (124.5 mg, 0.187 mmol) at 0° C. The mixturewas stirred at 0° C. for 1 hour. After concentration, the residue waspurified by prep-HPLC (5%-95% ACN in H₂O) to afford the product (25 mg,29% yield) as white powder. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (s, 1H),7.20-7.15 (m, 1H), 7.04-6.93 (m, 2H), 6.62-6.53 (m, 1H), 6.39-6.52 (m,1H), 5.75 (d, J=9.2 Hz, 1H), 5.37-5.28 (m, 1H), 4.72-4.68 (m, 1H),4.51-4.26 (m, 2H), 3.99-3.38 (m, 5H), 3.11-2.97 (m, 2H), 2.82-2.76 (m,3H), 2.59-2.37 (m, 8H), 1.26-1.22 (m, 3H), 1.09 (t, J=7.2 Hz, 3H). MS(ESI) m/z 663.3 [M+H]⁺

F. Example 352(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(2,4-difluorophenyl)-3-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

(3S)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-3-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(2)

To a solution of (3S)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-5-oxo-3-(piperazin-1-ylmethyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(150 mg, 0.22 mmol) and oxetan-3-one (158 mg, 2.2 mmol) in DCM was addedsodium triacetoxyborohydride (27 mg, 0.44 mmol). The mixture was stirredat 20° C. for 2 hours. After removing solvent in vacuo, the residue waspurified by silica gel column chromatography(dichloromethane/methanol=30/1) to give the product (150 mg, crude) asyellow solid. MS (ESI) m/z 737.2 [M+H]⁺

(3S)-10-(2,4-difluorophenyl)-7-((S)-2-methylpiperazin-1-yl)-3-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(3)

To a solution of(3S)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-3-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(150 mg, crude) in DCM (3 mL) was added TFA (0.8 mL). The mixture wasstirred at 20° C. for 1 hours. The mixture was concentrated to give thecrude product as the TFA salt (160 mg, crude) which was used in nextstep without further purification.

(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(2,4-difluorophenyl)-3-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(4)

To a solution of(3S)-10-(2,4-difluorophenyl)-7-((S)-2-methylpiperazin-1-yl)-3-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(130 mg, 0.18 mmol) and triethyl amine (61 mg, 0.60 mmol) in DCM (3 mL)was added acrylic anhydride (51.0 mg, 0.41 mmol) at 0° C. The mixturewas stirred at 0° C. for 1 hour. After removing solvent in vacuo, theresidue was purified by prep-HPLC (5%-95% ACN in H₂O) to afford theproduct (24 mg, 0.04 mmol) as white powder. 1H NMR (400 MHz, CDCl₃) δ7.77 (s, 1H), 7.21-7.15 (m, 1H), 7.04-6.93 (m, 2H), 6.65-6.35 (m, 2H),5.78 (d, J=8.4 Hz, 1H), 5.33-5.30 (m, 1H), 4.69-4.42 (m, 7H), 3.80-3.40(m, 6H), 3.08-2.99 (m, 2H), 2.88-2.74 (m, 3H), 2.58-2.53 (m, 3H),2.31-2.17 (m, 3H), 1.49-1.48 (m, 3H). MS (ESI) m/z 691.2 [M+H]⁺

G. Example 353(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(2,4-difluorophenyl)-3-((1-ethylpiperidin-4-yl)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

benzyl4-((2R)-3-((7-(2,4-difluorophenyl)-4-hydroxy-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-8-yl)thio)-2-hydroxypropyl)-5,6-dihydropyridine-1(2H)-carboxylate (2)

A mixture of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(1.17 g, 2.5 mmol), (R)-benzyl4-(2-hydroxy-3-mercaptopropyl)-5,6-dihydropyridine-1(2H)-carboxylate(1.0 g, 3.25 mmol), CuI (381 mg, 2.0 mmol) and K₂CO₃ (1.04 g, 7.5 mmol)in ethane-1,2-diol (10 mL) and i-PrOH (10 mL) was stirred under nitrogenatmosphere at 85° C. for 4 hours. After completion, the mixture wasconcentrated and the residue was purified by silica gel column using amixture of DCM/EA (3:1) to afford the desired product (725 mg, 1.12mmol, 44% yield) as a light yellow solid. MS (ESI) m/z 648.7 [M+H]8.

benzyl4-(((3S)-10-(2,4-difluorophenyl)-7-hydroxy-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)-5,6-dihydropyridine-1(2H)-carboxylate(3)

To a solution of benzyl4-((2R)-3-((7-(2,4-difluorophenyl)-4-hydroxy-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-8-yl)thio)-2-hydroxypropyl)-5,6-dihydropyridine-1(2H)-carboxylate(525 mg, 0.81 mmol) and triphenylphosphine (850 mmol, 3.25 mmol) in THF(150 mL) was added DEAD (566 mg, 3.25 mmol) slowly at 0° C. undernitrogen atmosphere. The mixture was stirred at room temperature for 1h. EtOAc (150 mL) was added. The organic phase was washed with water(100 mL×2), dried over Na₂SO₄, filtered and concentrated. The residuewas purified by C18 with 30-95% ACN in H₂O to afford the desired product(390 mg, 0.62 mmol, yield: 77%) as a light yellow solid. MS (ESI) m/z630.7 [M+H]⁺.

(3S)-tert-butyl4-((3S)-3-((1-((benzyloxy)carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)methyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(4)

To a solution of benzyl4-(((3S)-10-(2,4-difluorophenyl)-7-hydroxy-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)-5,6-dihydropyridine-1(2H)-carboxylate(390 mg, 0.62 mmol) and K₂CO₃ (856 mg, 6.2 mmol) in ACN (8 mL) was addedTs₂O (304 mg, 0.93 mmol). The mixture was stirred at rt for 5 h. Afterthe reaction was completed, (S)-tert-butyl3-methylpiperazine-1-carboxylate (372 mg, 1.86 mmol) was added. Theresulting mixture was stirred at rt for 20 min. After removing solventin vacuo, the residue was purified by C18 with 30-95% ACN in H₂O toafford desired product (280 mg, yield: 56%) as yellow solid. MS (ESI)m/z 812.2 [M+H]⁺.

(3S)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-5-oxo-3-(piperidin-4-ylmethyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(5)

The mixture of (3S)-tert-butyl4-((3S)-3-((1-((benzyloxy)carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)methyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(240 mg, 0.296 mmol) and Pd/C (500 mg) in EtOH was stirred underhydrogen atmosphere (50 psi) for 18 hours. After filtration, thefiltrate was concentrated to afford crude product (200 mg, crude) asyellow solid. MS (ESI) m/z 680.1 [M+H]⁺.

(3S)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-3-((1-ethylpiperidin-4-yl)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(6)

To a mixture of (3S)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-5-oxo-3-(piperidin-4-ylmethyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(200 mg, 0.296 mmol) and acetaldehyde (0.5 mL, 40% in water) in EtOH wasadded sodium triacetoxyborohydride (125 mg, 0.59 mmol). The mixture wasstirred at 20° C. for 2 hours. After removing solvent in vacuo, theresidue was purified by silica gel column chromatography(dichloromethane/methanol=30/1) to give the product (124 mg, 59% yield)as yellow solid. MS (ESI) m/z 708.2 [M+H]⁺

(3S)-10-(2,4-difluorophenyl)-3-((1-ethylpiperidin-4-yl)methyl)-7-((S)-2-methylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(7)

To the mixture of (3S)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-3-((1-ethylpiperidin-4-yl)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(124 mg, 0.17 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture wasstirred at 20° C. for 2 hours. The mixture was concentrated to give thecrude product as the TFA salt which was used in next step withoutfurther purification.

(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(2,4-difluorophenyl)-3-((1-ethylpiperidin-4-yl)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a mixture of(3S)-10-(2,4-difluorophenyl)-3-((1-ethylpiperidin-4-yl)methyl)-7-((S)-2-methylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(100 mg, 0.165 mmol) and triethyl amine (33 mg, 0.33 mmol) in DCM (2 mL)was added acrylic anhydride (21 mg, 0.165 mmol) at 0° C. The mixture wasstirred at 0° C. for 1 hour. After removing solvent in vacuo, theresidue was purified by silica gel column with DCM/MeOH (containing 5%NH₃)=30/1 to afford the product (40 mg, 37% yield) as white powder. ¹HNMR (400 MHz, CDCl₃) δ 7.79 (s, 1H), 7.29-7.15 (m, 1H), 7.06-6.95 (m,2H), 6.61-6.53 (m, 1H), 6.37 (d, J=15.6 Hz, 1H), 5.78 (d, J=6.0 Hz, 1H),5.43-5.38 (m, 1H), 4.71-4.69 (m, 1H), 4.52-4.27 (m, 2H), 3.98-3.95 (m,0.5H), 3.83-3.80 (m, 0.5H), 3.61-3.43 (m, 2H), 3.13-2.92 (m, 5H), 2.42(q, J=7.2 Hz, 2H), 2.01-1.90 (m, 3H), 1.78-1.72 (m, 3H), 1.52-1.32 (m,6H), 1.09 (t, J=7.2 Hz, 3H). MS (ESI) m/z 662.2 [M+H]⁺.

H. Example 354(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-3-((4-ethylpiperazin-1-yl)methyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

(R)-benzyl4-(3-((7-bromo-6-chloro-4-hydroxy-2-oxo-1,2-dihydroquinazolin-8-yl)thio)-2-hydroxypropyl)piperidine-1-carboxylate(2)

The mixture of 7-bromo-6-chloro-8-iodoquinazoline-2,4(1H,3H)-dione (4.9g, 12.25 mmol), (R)-benzyl4-(2-hydroxy-3-mercaptopropyl)piperidine-1-carboxylate (5.3 g, 17.15mmol), Pd₂(dba)₃ (1.13 g, 1.23 mmol), XantPhos (1.06 g, 1.84 mmol) andK₂CO₃ (3.38 g, 24.5 mmol) in dioxane (60 mL) was stirred under nitrogenatmosphere at 50° C. for 18 hours. After removing solvent in vacuo, theresidue was purified by silica gel column with a mixture of DCM/EA (3/1)to afford the product (3.8 g, yield: 54%) as a light yellow solid. MS(ESI) m/z 584.5 [M+H]⁺.

(S)-benzyl4-((10-bromo-9-chloro-7-hydroxy-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperidine-1-carboxylate(3)

To a mixture of (R)-benzyl4-(3-((7-bromo-6-chloro-4-hydroxy-2-oxo-1,2-dihydroquinazolin-8-yl)thio)-2-hydroxypropyl)piperidine-1-carboxylate(3.38 g, 5.8 mmol) and triphenylphosphine (6.08 g, 23.2 mmol) in THF(1000 mL) was added DEAD (4.04 g, 23.2 mmol) slowly at 0° C. undernitrogen atmosphere. The mixture was stirred at room temperature for 1h. The reaction mixture was concentrated and the residue was purified byC18 with 30-95% ACN in H₂O to afford the product (2.4 g, 73% yield) as alight yellow solid. MS (ESI) m/z 566.5 [M+H]⁺.

(S)-tert-butyl4-((S)-3-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-10-bromo-9-chloro-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(4)

To a solution of (S)-benzyl4-((10-bromo-9-chloro-7-hydroxy-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperidine-1-carboxylate(1.2 g, 2.12 mmol) and K₂CO₃ (2.9 g, 21.2 mmol) in ACN (50 mL) was addedTs₂O (1.38 g, 4.24 mmol). The mixture was stirred at rt for 5 h. Afterthe reaction was completed, (S)-tert-butyl3-methylpiperazine-1-carboxylate (1.2 g, 6.36 mmol) was added. Theresulting mixture was stirred at rt for 20 min. After removing thesolvent in vacuo, the residue was purified by C18 with 30-95% ACN in H₂Oto afford desired product (1.2 g, 80% yield) as yellow solid. MS (ESI)m/z 746.0 [M+H]⁺.

(3S)-tert-butyl4-((3S)-3-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-9-chloro-10-(2,4-difluorophenyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(5)

To a mixture of (S)-tert-butyl4-((S)-3-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-10-bromo-9-chloro-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(1.15 g, 1.5 mmol) and (2,4-difluorophenyl)boronic acid (1.2 g, 7.5mmol) in dioxane (20 mL) and H₂O (4 mL) was added Pd(dppf)Cl₂ (219 mg,0.3 mmol) and K₃PO₄ (954 mg, 4.5 mmol). The mixture was stirred at 80°C. under N₂ for 12 hours. After filtration, the filtrate wasconcentrated to afford crude product (1.3 g, crude) as yellow solid. MS(ESI) m/z 780.1 [M+H]⁺.

(3S)-tert-butyl4-((3S)-9-chloro-10-(2,4-difluorophenyl)-5-oxo-3-(piperidin-4-ylmethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(6)

The mixture of (3S)-tert-butyl4-((3S)-3-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-9-chloro-10-(2,4-difluorophenyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(1.3 g, 1.6 mmol) and Pd/C (1.3 g) in EtOH was stirred under hydrogenatmosphere for 4 hours. After filtration, the filtrate was concentratedto afford crude product (850 mg, crude) as yellow solid. MS (ESI) m/z646.8 [M+H]⁺.

(3S)-tert-butyl4-((3S)-9-chloro-10-(2,4-difluorophenyl)-3-((1-ethylpiperidin-4-yl)methyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(7)

To a mixture of (3S)-tert-butyl4-((3S)-9-chloro-10-(2,4-difluorophenyl)-5-oxo-3-(piperidin-4-ylmethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(200 mg, 0.3 mmol) and acetaldehyde (0.5 mL, 40% in water) in EtOH wasadded sodium triacetoxyborohydride (98 mg, 0.46 mmol). The mixture wasstirred at 20° C. for 2 hours. After removing the solvent in vacuo, andthe residue was purified by silica gel column chromatography(dichloromethane/methanol=10/1) to give the desired product (180 mg, 89%yield) as yellow solid. MS (ESI) m/z 674.2 [M+H]⁺.

(3S)-9-chloro-10-(2,4-difluorophenyl)-3-((1-ethylpiperidin-4-yl)methyl)-7-((S)-2-methylpiperazin-1-yl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To the mixture of (3S)-tert-butyl4-((3S)-9-chloro-10-(2,4-difluorophenyl)-3-((1-ethylpiperidin-4-yl)methyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(180 mg, 0.27 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture wasstirred at 20° C. for 2 hours. The reaction mixture was concentrated togive the crude product as the TFA salt, which was used in next stepwithout further purification.

(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-3-((1-ethylpiperidin-4-yl)methyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9)

To a mixture of(3S)-10-(2,4-difluorophenyl)-3-((1-ethylpiperidin-4-yl)methyl)-7-((S)-2-methylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(100 mg, 0.17 mmol) and triethyl amine (34 mg, 0.34 mmol) in DCM (2 mL)was added acrylic anhydride (22 mg, 0.17 mmol) at 0° C. The mixture wasstirred at 0° C. for 1 hour. After removing solvent in vacuo, theresidue was purified by prep-HPLC with a mixture of 5-95% ACN in H₂O toafford the desired product (30 mg, 28% yield) as white powder. ¹H NMR(400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.24-7.18 (m, 1H), 7.07-6.95 (m, 2H),6.67-6.52 (m, 1H), 6.36 (d, J=16.8 Hz, 1H), 5.75 (d, J=10.4 Hz, 1H),5.41-5.28 (m, 1H), 4.74-4.66 (m, 1H), 4.56-4.54 (m, 0.5H), 4.48-4.35 (m,1H), 4.22-4.16 (m, 0.5H), 3.99-3.77 (m, 1H), 3.59-3.39 (m, 3H),3.09-3.00 (m, 2H), 2.84-2.76 (m, 3H), 2.55-2.35 (m, 9H), 1.48-1.43 (m,3H), 1.08-1.04 (m, 3H). MS (ESI) m/z 629.3 [M+H]⁺.

I. Example 355(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-3-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

(3S)-tert-butyl4-((3S)-9-chloro-10-(2,4-difluorophenyl)-3-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(2)

To a solution of (3S)-tert-butyl4-((3S)-9-chloro-10-(2,4-difluorophenyl)-5-oxo-3-(piperazin-1-ylmethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(200 mg, 0.31 mmol) and oxetan-3-one (1.5 mL) in DCM (1.5 mL) was addedsodium triacetoxyborohydride (88 mg, 0.44 mmol). The mixture was stirredat 20° C. for 2 hours. After removing the solvent in vacuo, the residuewas purified by silica gel column chromatography(dichloromethane/methanol=30/1) to give the desired product (120 mg, 55%yield) as yellow solid. MS (ESI) m/z 703.2 [M+H]⁺

(3S)-9-chloro-10-(2,4-difluorophenyl)-7-((S)-2-methylpiperazin-1-yl)-3-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(3)

To a solution of (3S)-tert-butyl4-((3S)-9-chloro-10-(2,4-difluorophenyl)-3-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(120 mg, 0.17 mmol) in dichloromethane (3 mL) was added TFA (1 mL) at 0°C. After removing the solvent in vacuo, the residue was purified bysilica gel column chromatography (dichloromethane/methanol=20/1) to givethe desired product (100 mg, crude) as yellow solid. LC-MS: m/z 603.1[M+H]⁺;

(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-3-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(4)

To a mixture of(3S)-9-chloro-10-(2,4-difluorophenyl)-7-((S)-2-methylpiperazin-1-yl)-3-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(80 mg, 0.13 mmol) and triethyl amine (26 mg, 0.26 mmol) indichloromethane (3 mL) was added acrylic anhydride (25 mg, 0.19 mmol) at0° C. The mixture was stirred at rt for 1 hour. After removing thesolvent in vacuo, the residue was purified by prep-HPLC to afford thedesired product (35 mg, 41% yield) as yellow solid. LC-MS: m/z 657.1[M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.24-7.18 (m, 1H), 7.07-6.95 (m,2H), 6.66-6.51 (m, 1H), 6.37 (d, J=16.4 Hz, 1H), 5.77 (d, J=10.8 Hz,1H), 5.40-5.27 (m, 1H), 4.71-4.58 (m, 5.5H), 4.52-4.36 (m, 1H), 4.20 (s,0.5H), 3.99-3.77 (m, 1H), 3.57-3.37 (m, 4H), 3.09-3.01 (m, 2H),2.85-2.87 (m, 3H), 2.57-2.55 (m, 3H), 2.35-2.31 (m, 4H), 1.48-1.43 (m,3H).

J. Example 356(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

(3S)-tert-butyl4-((3S)-9-chloro-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(2)

To a solution of (3S)-tert-butyl4-((3S)-9-chloro-10-(2,4-difluorophenyl)-5-oxo-3-(piperidin-4-ylmethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(210 mg, 0.32 mmol) and 1,1-difluoro-2-iodoethane (311 mg, 1.62 mmol) inACN (10 mL) was added K₂CO₃ (224 mg, 1.62 mmol). The mixture stirred wasat 85° C. for 16 hours. After removing solvent in vacuo, the residue waspurified by silica gel column chromatography(dichloromethane/methanol=40/1) to give the desired product (130 mg, 56%yield) as yellow solid. MS (ESI) m/z 711.8 [M+H]⁺

(3S)-9-chloro-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-7-((S)-2-methylpiperazin-1-yl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(3)

To a solution of (3S)-tert-butyl4-((3S)-9-chloro-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(130 mg, 0.18 mmol) in dichloromethane (3 mL) was added TFA (1 mL) at 0°C. After removing solvent in vacuo, the residue was purified by silicagel column chromatography (dichloromethane/methanol=20/1) to give theproduct (92 mg, 84% yield) as yellow solid. LC-MS: m/z 611.7 [M+H]⁺;

(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(4)

To a solution of(3S)-9-chloro-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-7-((S)-2-methylpiperazin-1-yl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(70 mg, 0.11 mmol) and triethyl amine (22 mg, 0.22 mmol) indichloromethane (3 mL) was added acrylic anhydride (25 mg, 0.19 mmol) at0° C. The mixture was stirred at rt for 1 hour. After removing solventin vacuo, the residue was purified by prep-HPLC to afford the product(41 mg, 42% yield) as yellow solid. LC-MS: m/z 665.8 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.24-7.18 (m, 1H), 7.07-6.95 (m,2H), 6.66-6.51 (m, 1H), 6.36 (d, J=16.8 Hz, 1H), 6.00-5.70 (m, 2H),5.40-5.32 (m, 1H), 4.71-4.65 (m, 1H), 4.56-4.35 (m, 1.5H), 4.23-4.17 (m,0.5H), 3.99-3.78 (m, 1H), 3.64-3.37 (m, 3H), 3.08-3.00 (m, 2H),2.84-2.67 (m, 5H), 2.58-2.52 (m, 7H), 1.48-1.43 (m, 3H).

K. Example 19(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

(3S)-tert-butyl4-((3S)-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(2)

To a mixture of (3S)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-5-oxo-3-(piperidin-4-ylmethyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(150 mg, 0.22 mmol), and 1,1-difluoro-2-iodoethane (211 mg, 1.1 mmol) inACN (5 mL) was added K₂CO₃ (91 mg, 0.66 mmol). The mixture was stirredat 85° C. for 16 hours. After removing solvent in vacuo, the residue waspurified by silica gel column chromatography(dichloromethane/methanol=40/1) to give the product (100 mg, 61% yield)as yellow solid. MS (ESI) m/z 745.1 [M+H]⁺

(3S)-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-7-((S)-2-methylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(3)

To a solution of (3S)-tert-butyl4-((3S)-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(100 mg, 0.13 mmol) in dichloromethane (3 mL) was added TFA (1 mL) at 0°C. for 1 hour. After removing solvent in vacuo, the residue was purifiedby silica gel column chromatography (dichloromethane/methanol=20/1) togive the desired product (150 mg, crude) as yellow solid. LC-MS: m/z645.1 [M+H]⁺;

(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(4)

To a mixture of(3S)-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-7-((S)-2-methylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(100 mg, 0.15 mmol) and triethyl amine (38 mg, 0.3 mmol) indichloromethane (3 mL) was added acrylic anhydride (25 mg, 0.19 mmol) at0° C. The mixture was stirred at rt for 1 hour. After removing thesolvent in vacuo, the residue was purified by prep-HPLC to afford theproduct (30 mg, 28% yield) as yellow solid. LC-MS: m/z 699.1 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.20-7.16 (m, 1H), 7.07-6.94 (m,2H), 6.71-6.51 (m, 1H), 6.41-6.35 (m, 1H), 6.00-5.69 (m, 2H), 5.38-5.32(m, 1H), 4.75-4.61 (m, 1H), 4.52-4.23 (m, 2H), 4.04-3.77 (m, 1H),3.67-3.39 (m, 3H), 3.16-2.80 (m, 2H), 2.79-2.66 (m, 5H), 2.61-2.52 (m,7H), 1.54-1.43 (m, 3H).

TABLE 5 Summary Table Ex. MS # Name Structure ¹H NMR (M + H)⁺ 137(R)-7-((S)-4-acryloyl- 2-methylpiperazin-1- yl)-9-chloro-3-(methoxymethyl)-10- (2,4,6- trifluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.52-7.49 (brs, 1H), 6.86-6.82 (m, 1H),6.60-6.56 (m, 1H), 6.39-6.35 (m, 1H), 5.78 (d, J = 2.4 Hz, 1H), 5.44(brs, 1H), 5.01-4.47 (m, 2H), 4.09-3.99 (m, 1.5H), 3.83-3.62 (m, 4H),3.49-3.32 (m, 5H), 3.05-3.01 (m, 1H), 2.90-2.85 (m, 0.5H), 2.64-2.45 (m,3H), 1.88-1.80 (m, 4H), 1.53-1.46 (m, 2H), 1.34 (d, J = 6.4 Hz, 3H).565.1 130 (3R)-7-((S)-4- acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-3- (methoxymethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.52-7.49 (brs, 1H), 7.24-7.19 (m, 1H),7.07-6.95(m, 2H), 6.59-6.57 (m, 1H), 6.39-6.32 (m, 1H), 5.78 (d, J = 2.4Hz, 1H), 5.43-5.39 (m, 1H), 5.01- 4.47 (m, 2H), 4.09-3.99 (m, 1.5H),3.83-3.62 (m, 4H), 3.49-3.32 (m, 5H), 3.06-3.01 (m, 1H), 2.90-2.85 (m,0.5H), 2.64-2.45 (m, 3H), 1.88-1.80 (m, 4H), 1.53-1.46 (m, 2H), 1.34 (d,J = 6.4 Hz, 3H). 547.1 99 (3R)-7-((S)-4- acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-3- methyl-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.51 (s, 1H), 7.25-7.19 (m, 1H), 7.07-6.97 (m,2H), 6.59- 6.57 (m, 1H), 6.39-6.36(d, 1H), 5.79-5.76(d, 1H), 5.42(s,1H), 4.96-4.86(d, 1H), 4.64- 4.62(d, 1H), 4.02-3.96(t, 1.5H),3.83-3.67(m, 2H), 3.42- 3.21(m, 2H), 2.92-2.87(m, 1.5H), 1.48-1.45(t,3H),1.33- 1.31(d, 3H). 517.1 339 (R)-3-(3-((1S,4S)-2- oxa-5-azabicyclo[2.2.1]hep- tan-5-yl)propyl)-7- ((S)-4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-10- (2,4,6- trifluorophenyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.51 (brs, 1H), 6.84 (t, J = 8.0 Hz, 1H),6.63-6.53(m, 1H), 6.39-6.35 (m, 1H), 5.78 (d, J = 11.2 Hz, 1H), 5.32(brs, 1H), 4.94-4.75 (m, 1H), 4.67- 4.55 (m, 1H), 4.38 (s, 1H),4.09-4.00 (m, 2H), 3.83-3.44 (m, 5H), 3.24-3.05 (m, 2H), 2.71-2.51 (m,3H), 1.95-1.88 (m, 4H), 1.58-1.53 (m, 2H), 1.36 (d, J = 7.2 Hz, 3H).660.2 340 (S)-3-(3-((1S,4S)-2- oxa-5- azabicyclo[2.2.1]hep-tan-5-yl)propyl)-7- ((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10- (2,4,6- trifluorophenyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.50 (s, 1H), 6.84 (t, J = 8.0 Hz, 1H),6.63-6.53(m, 1H), 6.39- 6.35 (m, 1H), 5.78 (d, J = 11.2 Hz, 1H), 5.32(brs, 1H), 4.70-4.25 (m, 4H), 4.09-3.96 (m, 2H), 3.61-3.41 (m, 4H),3.26-2.93 (m, 4H), 2.71-2.51 (m, 3H), 1.95-1.84 (m, 4H), 1.52-1.45 (m,3H). 660.2 341 (3R)-3-(3-((1S,4S)-2- oxa-5- azabicyclo[2.2.1]hep-tan-5-yl)propyl)-7- ((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2,4- difluorophenyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.50 (brs, 1H), 7.24-7.19 (m, 1H), 7.07-6.96(m, 2H), 6.59- 6.52 (m, 1H), 6.39-6.32 (m, 1H), 5.78 (d, J = 2.4 Hz,1H), 5.32 (brs, 1H), 4.93-4.63 (m, 4H), 4.37-4.36 (m, 2H), 4.09- 3.98(m, 2.5H), 3.83-3.57 (m, 3H), 3.45-3.25 (m, 2H), 3.14- 3.04 (m, 2.5H),2.90-2.87 (m, 1H), 2.64-2.45 (m, 3H), 1.88- 1.80 (m, 4H), 1.53-1.46 (m,2H), 1.34 (d, J = 6.8 Hz, 3H). 642.3 342 (3S)-3-(3-((1S,4S)-2- oxa-5-azabicyclo[2.2.1]hep- tan-5-yl)propyl)-7- ((S)-4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-10-(2,4- difluorophenyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.49 (s, 1H), 7.26-7.18 (m, 1H), 7.07-6.95 (m,2H), 6.62- 6.53 (m, 1H), 6.39-6.36 (d, 1H), 5.79-5.78 (d, 1H), 5.34-5.28 (m, 1H), 4.74-4.70 (m, 1H), 4.54-4.23 (m, 3H), 3.99- 3.96 (dd,1.5H), 3.81-3.45 (m, 4.5H), 3.09-2.86 (m, 4H), 2.7- 2.46 (m, 3H),1.92-1.75 (m, 4H),1.66-1.36 (m, 5H). 642.2 343 (S)-7-((S)-4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-3-((1- methylpiperidin-4-yl)methyl)-10-(2,4,6- trifluorophenyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.51 (s, 1H), 6.85 (t, J = 8.0 Hz, 2H),6.63-6.54 (m, 1H), 6.40- 6.36 (m, 1H), 5.78 (d, J = 9.6 Hz, 1H),5.47-5.46 (m, 1H), 4.75-4.66 (m, 1H), 4.57-4.43 (m, 1H), 4.38-4.18 (m,1H), 3.97-3.79 (m, 1H), 3.61-3.46 (m, 2H), 3.19-3.16 (m, 1H), 3.09-2.98(m, 2H), 2.89-2.84 (m, 2H), 2.27 (s, 3H), 2.02- 1.91 (m, 2.5H),1.81-1.76 (m, 2.5H), 1.48-1.31 (m, 7H). 632.2 344 (R)-7-((S)-4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-3-((1- methylpiperidin-4-yl)methyl)-10-(2,4,6- trifluorophenyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.52-7.51 (m, 1H), 6.85 (t, J = 8.0 Hz, 2H),6.63-6.53 (m, 1H), 6.38 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.78 (d, J = 10.8Hz, 1H), 5.48-5.46 (m, 1H), 4.91- 4.89 (m, 0.5H), 4.74-4.64 (m, 1H),4.50-4.47 (m, 0.5H), 4.17-3.97 (m, 1.5H), 3.84-3.46 (m, 3H), 3.20-3.16(m, 1.5H), 3.02-2.92 (m, 1.5H), 2.87-2.81 (m, 2H), 2.25 (s, 3H), 1.99-1.84 (m, 2.5H), 1.64-1.58 (m, 2H), 1.44-1.32 (m, 7H). 632.2 345(3R)-7-((S)-4- acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(2,4-difluorophenyl)-3-((1- methylpiperidin-4- yl)methyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.51 (s, 1H), 7.24-7.20 (m, 1H), 7.07-6.96 (m,2H), 6.59- 6.57 (m, 1H), 6.37 (d, J = 15.6 Hz, 1H), 5.78 (d, J = 10.8Hz, 1H), 5.48-5.42 (m, 1H), 4.91- 4.89 (m, 0.5H), 4.71-4.63 (m, 1H),4.48-4.47 (m, 0.5H), 4.12-3.98 (m, 1.5H), 3.83-3.49 (m, 3H), 3.22-3.11(m, 1.5H), 2.99-2.86 (m, 3.5H), 2.30 (s, 3H), 1.98-1.91 (m, 1.5H),1.51-1.33 (m, 10H). 614.2 346 (3R)-7-((S)-4- acryloyl-2-methylpiperazin-1- yl)-9-chloro-10-(2,4- difluorophenyl)-3-((4-ethylpiperazin-1- yl)methyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.51-7.49 (m, 1H), 7.24-7.18 (m, 1H),7.07-6.95 (m, 2H), 6.61-6.53 (m, 1H), 5.78 (d, J = 11.2 Hz, 1H),5.38-5.31 (m, 1H), 4.990-4.46 (m, 2H), 4.19- 4.00 (m, 1.5H), 3.83-3.40(m, 3.5H), 3.14-2.98 (m, 2H), 2.84-2.65 (m, 3H), 2.54-2.30 (m, 9H), 1.36(d, J = 6.4 Hz, 2H), 1.08-1.02 (m, 3H). 629.3 76 7-((5)-4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-10-(2,4- difluorophenyl)-2,2-dimethyl-2,3-dihydro- 5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, MeOH- d₄) δ 7.71 (d, J = 4.5 Hz, 1H), 7.33-7.22 (m,1H), 7.18-7.09 (m, 2H), 6.91-6.73 (m, 1H), 6.29 (dd, J = 16.2. 7.2 Hz,1H), 5.81 (dd, J = 10.6. 1.9 Hz, 1H), 4.68-3.93 (m, 5H), 3.80-3.45 (m,2H), 1.42 (s, 3H), 1.38 (s, 3H) 531.2 347 (3R)-7-((S)-4- acryloyl-2-methylpiperazin-1- yl)-9-chloro-3-((4- (2,2- difluoroethyl)piperazin-1-yl)methyl)-10- (2,4-difluorophenyl)- 2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.49 (brs, 1H), 7.23-7.17 (m, 1H), 7.07-6.95(m, 2H), 6.62- 6.55 (m, 1H), 6.39-6.34 ( m, 1H), 6.01-5.70 (m, 2H),5.38- 5.30 (m, 1H), 4.92-4.54(m, 2H),4.11-3.99 (m, 1.5H), 3.82- 3.21(m,4.5H), 3.02-2.83 (m, 2H), 2.74-2.67 (m, 5H), 2.60- 2.52 (m, 7H), 1.45(d, J = 6.8 Hz, 3H). 665.2 348 (3R)-7-((S)-4- acryloyl-2-methylpiperazin-1- yl)-9-chloro-3-((1- (2,2- difluoroethyl)piperidin-4-yl)methyl)-10- (2,4-difluorophenyl)- 2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.51 (s, 1H), 7.24-7.20 (m, 1H), 7.07-6.96 (m,2H), 6.62- 6.53 (m, 1H), 6.37 (dd, J = 16.4 Hz, 1.2 Hz, 1H), 6.00- 5.71(m, 2H), 5.44-5.43 (m, 1H), 4.91-4.88 (m, 0.5 H), 4.72-4.63 (m, 1H),4.48-4.45 (m, 0.5H), 4.13-3.96 (m, 1.5H), 3.83-3.62 (m, 1.5H), 3.59-3.45(m, 1H), 3.23- 3.20(m, 0.5H), 3.18-3.10 (m, 1H), 2.99-2.87 (m, 3.5H),2.74-2.65 (m, 2H), 2.24-2.14 (m, 2H), 1.75-1.73 (m, 3H), 1.45-1.35 (m,7H). 664.3 349 (R)-7-((S)-4-acryloyl- 2-methylpiperazin-1-yl)-9-chloro-3-((1- (2,2- difluoroethyl)piperidin- 4-yl)methyl)-10-(4-fluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.51 (s, 1H), 7.25-7.19 (m, 4H), 6.63-6.52 (m,1H), 6.37 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 6.01-5.71 (m, 2H), 5.43-5.41(m, 1H), 4.91-4.88 (m, 0.5 H), 4.71-4.63 (m, 1H), 4.49-4.46 (m, 0.5H),4.15-4.00 (m, 1.5H), 3.83-3.64 (m, 1.5H), 3.61-3.47 (m, 1H), 3.23-3.21(m, 0.5H), 3.10-3.06 (m, 1H), 2.96-2.89 (m, 3.5H), 2.75-2.66 (m, 2H),2.23-2.13 (m, 2H), 1.87-1.74 (m, 4H), 1.47-1.33 (m, 6H). 646.2 350(3S)-7-((S)-4- acryloyl-2- methylpiperazin-1- yl)-10-(2,4-difluorophenyl)-3-((4- ethylpiperazin-1- yl)methyl)-9-(trifluoromethyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.75 (s, 1H), 7.20-7.15 (m, 1H), 7.04-6.93 (m,2H), 6.62- 6.53 (m, 1H), 6.39-6.52 (m, 1H), 5.75 (d, J = 9.2 Hz, 1H),5.37-5.28 (m, 1H), 4.72-4.68 (m, 1H), 4.51-4.26 (m, 2H), 3.99-3.38 (m,5H), 3.11-2.97 (m, 2H), 2.82-2.76 (m, 3H), 2.59-2.37 (m, 8H), 1.26-1.22(m, 3H), 1.09 (t, J = 7.2 Hz, 3H). 663.3 351 (S)-7-((S)-4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-3-((4- ethylpiperazin-1-yl)methyl)-10-(2,4,6- trifluorophenyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.49 (s, 1H), 6.86-6.82 (m, 2H), 6.70-6.48 (m,1H), 6.39- 6.34 (m, 1H), 5.79-5.76 (m, 1H), 5.45-5.33 (m, 1H), 4.76-4.64 (m, 1H), 4.61-4.24 (m, 1.5H), 4.14-4.01 (m, 0.5H), 4.01-3.74 (m,1H), 3.62-3.41 (m, 3H), 3.08-3.05 (m, 2H), 2.82-2.78 (m, 3H), 2.55-2.36(m, 9H), 1.48-1.43 (m, 3H), 1.09-1.05 (m, 3H) 647.2 352 (3S)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-10-(2,4- difluorophenyl)-3-((4-(oxetan-3- yl)piperazin-1- yl)methyl)-9- (trifluoromethyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.21-7.15 (m, 1H), 7.04-6.93 (m,2H), 6.65- 6.35 (m, 2H), 5.78 (d, J = 8.4 Hz, 1H), 5.33-5.30 (m, 1H),4.69-4.42 (m, 7H), 3.80- 3.40 (m, 6H), 3.08-2.99 (m, 2H), 2.88-2.74 (m,3H), 2.58- 2.53 (m, 3H), 2.31-2.17 (m, 3H), 1.49-1.48 (m, 3H). 691.2 353(3S)-7-((S)-4- acryloyl-2- methylpiperazin-1- yl)-10-(2,4-difluorophenyl)-3-((1- ethylpiperidin-4- yl)methyl)-9-(trifluoromethyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.79 (s, 1H), 7.29-7.15 (m, 1H), 7.06-6.95 (m,2H), 6.61- 6.53 (m, 1H), 6.37 (d, J = 15.6 Hz, 1H), 5.78 (d, J = 6.0 Hz,1H), 5.43-5.38 (m, 1H), 4.71- 4.69 (m, 1H), 4.52-4.27 (m, 2H), 3.98-3.95(m, 0.5H), 3.83-3.80 (m, 0.5H), 3.61-3.43 (m, 2H), 3.13-2.92 (m, 5H),2.42 (q, J = 7.2 Hz, 2H), 2.01- 1.90 (m, 3H), 1.78-1.72 (m, 3H),1.52-1.32 (m, 6H), 1.09 (t, J = 7.2 Hz, 3H). 662.2 354 (3S)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(2,4-difluorophenyl)-3-((4- ethylpiperazin-1- yl)methyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.24-7.18 (m, 1H), 7.07-6.95 (m,2H), 6.67- 6.52 (m, 1H), 6.36 (d, J = 16.8 Hz, 1H), 5.75 (d, J = 10.4Hz, 1H), 5.41-5.28 (m, 1H), 4.74- 4.66 (m, 1H), 4.56-4.54 (m, 0.5H),4.48-4.35 (m, 1H), 4.22-4.16 (m, 0.5H), 3.99-3.77 (m, 1H), 3.59-3.39 (m,3H), 3.09-3.00 (m, 2H), 2.84-2.76 (m, 3H), 2.55-2.35 (m, 9H), 1.48-1.43(m, 3H), 1.08-1.04 (m, 3H). 629.3 355 (3S)-7-((S)-4- acryloyl-2-methylpiperazin-1- yl)-9-chloro-10-(2,4- difluorophenyl)-3-((4-(oxetan-3- yl)piperazin-1- yl)methyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.24-7.18 (m, 1H), 7.07-6.95 (m,2H), 6.66- 6.51 (m, 1H), 6.37 (d, J = 16.4 Hz, 1H), 5.77 (d, J = 10.8Hz, 1H), 5.40-5.27 (m, 1H), 4.71- 4.58 (m, 5.5H), 4.52-4.36 (m, 1H),4.20 (s, 0.5H), 3.99-3.77 (m, 1H), 3.57-3.37 (m, 4H), 3.09-3.01 (m, 2H),2.85-2.87 (m, 3H), 2.57-2.55 (m, 3H), 2.35-2.31 (m, 4H), 1.48-1.43 (m,3H). 657.3 356 (3S)-7-((S)-4- acryloyl-2- methylpiperazin-1-yl)-9-chloro-3-((4- (2,2- difluoroethyl)piperazin- 1-yl)methyl)-10-(2,4-difluorophenyl)- 2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.24-7.18 (m, 1H), 7.07-6.95 (m,2H), 6.66- 6.51 (m, 1H), 6.36 (d, J = 16.8 Hz, 1H), 6.00-5.70 (m, 2H),5.40-5.32 (m, 1H), 4.71-4.65 (m, 1H), 4.56-4.35 (m, 1.5H), 4.23-4.17 (m,0.5H), 3.99-3.78 (m, 1H), 3.64-3.37 (m, 3H), 3.08-3.00 (m, 2H),2.84-2.67 (m, 5H), 2.58-2.52 (m, 7H), 1.48-1.43 (m, 3H). 665.3 19(3S)-7-((S)-4- acryloyl-2- methylpiperazin-1- yl)-3-((4-(2,2-difluoroethyl)piperazin- 1-yl)methyl)-10- (2,4-difluorophenyl)-9-(trifluoromethyl)- 2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.20-7.16 (m, 1H), 7.07-6.94 (m,2H), 6.71- 6.51 (m, 1H), 6.41-6.35 (m, 1H), 6.00-5.69 (m, 2H), 5.38-5.32 (m, 1H), 4.75-4.61 (m, 1H), 4.52-4.23 (m, 2H), 4.04- 3.77 (m, 1H),3.67-3.39(m, 3H), 3.16-2.80 (m, 2H), 2.79- 2.66(m, 5H), 2.61-2.52(m,7H), 1.54-1.43(m, 3H). 699.6

Syntheses of Intermediates

2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (2)

To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (100 g, 0.43 mol)in DMF (800 mL) was added NCS (68 g, 0.51 mol). Then the mixture washeated to 70° C. for 16 hours. After completion, the mixture wasquenched with aqueous H₂O (1.5 L) and extracted with EA (2 L), driedwith Na₂SO₄ and concentrated to afford product (139 g, crude) as agrayness solid. LC-MS: m/z 268.1 [M−H]⁺

7-bromo-6-chloro-8-fluoroquinazoline-2,4-diol (3)

The mixture of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (139 g,0.51 mol) and urea (260 g, 4.33 mol) was heated to 180° C. for 6 h.After completion, the mixture was quenched with aqueous H₂O (1.5 L),filtered through a Celite pad, and the filtrate was concentrated to givethe crude product (130 g, crude) as a grayness solid. LC-MS: m/z 293.1[M−H]⁺

7-bromo-2,4,6-trichloro-8-fluoroquinazoline (4)

The mixture of 7-bromo-6-chloro-8-fluoroquinazoline-2,4-diol (130 g,0.51 mol) and POCl₃ (800 mL) was heated to 120° C. for 16 hours. Aftercompletion, the mixture was quenched with aqueous H₂O (1.5 L), filteredthrough a Celite pad, and the filtrate was concentrated and purified bysilica column with PE/EA=4:1 to afford product (59 g, 35% yield) as ayellow solid. LC-MS: m/z 311.1 [M−H—Cl]⁺

(2R,5S)-tert-butyl-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate(5)

To a cooled mixture of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (25g, 75.76 mmol) and Et₃N (15.3 g, 151.5 mmol) in THF (200 mL) was added(2R,5S)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate (16.2 g, 75.76mmol) at 0° C. The mixture was stirred at room temperature for 4 hours.After completion, the mixture was dissolved with EtOAc (500 mL), washedwith water (300 mL×3), dried over Na₂SO₄, filtered and concentrated toafford desired product (35.78 g, yield: 93%) as yellow solid, which wasused to next step without further purification. LC-MS: m/z 509.3 [M+H].

(2R,5S)-tert-butyl-4-(7-bromo-2,8-di-tert-butoxy-6-chloroquinazolin-4-yl)-2,5-dimethyl-piperazine-1-carboxylate(6)

To a solution of (2R,5S)-tert-butyl4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (35.78 g, 70.4 mmol) in dry THF (180 mL) wasadded t-BuONa (16.9 g, 176.08 mmol). Then the mixture was heated to 60°C. for 4 hours. After completion, the mixture was quenched with aqueousNH₄Cl and extracted with EtOAc, dried with Na₂SO₄ and concentrated. Theresidue was purified by silica using a mixture of PE:EA (15:1) as eluentto afford product (33 g, 78% yield) as a yellow solid. LC-MS: m/z 601.5[M+H].

(2R,5S)-tert-butyl-4-(7-bromo-6-chloro-2,8-dihydroxyquinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (7)

To a solution of(2R,5S)-tert-butyl-4-(7-bromo-2,8-di-tert-butoxy-6-chloroquinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate(33 g, 55.0 mmol) in DCM (70 mL) was added TFA (70 mL), the mixture wasstirred at 25° C. for 3 hours. After completion, the mixture wasconcentrated under reduce pressure to afford the crude7-bromo-6-chloro-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)quinazoline-2,8-diol (30 g), which was used in the next step withoutfurther purification. To a solution of7-bromo-6-chloro-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)quinazoline-2,8-diol(33 g, 85.05 mmol) in DCM (150 mL) was added (Boc)₂O (18.54 g, 85.05mmol), the mixture was stirred at rt for 16 hours. After completion, themixture was concentrated. The residue was purified by silica with amixture of DCM/MeOH (5% NH₃) (40:1) to afford the desired product (24 g,58% yield) as light green solid. LC-MS: m/z 489.3 [M+H].

TABLE 7 Table of Thiomorpholines MS Ex. # Name Structure ¹H NMR (M + H)⁺408 7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(5-fluoro-1H-indazol- 4-yl)-2,3-dihydro- 5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, MeOH-d₄) δ 7.75 (br s, 1H), 7.72 (d, J = 7.4 Hz, 1H),7.25 (dd, J = 10.9, 7.8 Hz, 1H), 7.00 (ddd, J = 7.9, 4.0, 1.8 Hz, 1H),6.83 (ddd, J = 21.7, 16.7, 10.5 Hz, 1H), 6.29 (dd, J = 16.5, 6.6 Hz,1H), 5.82 (dd, J = 10.6, 1.9 Hz, 1H), 4.85-4.78 (m, 1H), 4.63-3.99 (m,5H), 3.78-3.44 (m, 2H), 3.25- 3.02 (m, 2H), 1.44 (d, J = 6.7 Hz, 1.5H),1.40 (d, J = 6.8 Hz, 1.5H). 525.2  408a 7-((S)-4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-10- (3,5-difluoropyridin- 2-yl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 8.53 (d, J = 2 Hz, 1H), 7.49 (s, 1H),7.42-7.38 (m, 1H), 6.61-6.52 (m, 1H), 6.40-6.36 (m, 1H), 5.78 (d, J = 10Hz, 1H), 4.69 (s, 0.5H), 4.66-4.50 (m, 3H), 4.29-4.15(m, 2H), 3.99- 3.96(m, 0.5H), 3.83-3.79 (m, 0.5H), 3,64-3.47 (m, 2H), 3.14- 3.04 (m, 2.5H),1.47-1.37 (m, 3H). 504.1 409 7-((S)-4-acryloyl-2- 1H NMR (400 MHz, 521.1methylpiperazin-1- MeOD) δ 7.59 (d, J = 6.9 yl)-9-chloro-10- Hz, 1H),7.42-7.04 (m, (2,4,5- 2H), 6.85-6.60 (m, 1H), trifluorophenyl)-2,3-6.27-6.10 (m, 1H), 5.71 dihydro-5H- (dd, J = 10.6, 1.9 Hz, 1H),[1,4]thiazino[2,3,4- 4.68 (s, 1H), 4.53-4.25 ij]quinazolin-5-one (m,2H), 4.23-3.84 (m, 3H), 3.68-3.31 (m, 2H), 3.18-2.85 (m, 3H), 1.30 (dd,J = 16.5, 6.7 Hz, 3H). 419 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(7- fluoro-1H-indazol- 4-yl)-2,3-dihydro- 5H-[1,4]thiazino [2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, MeOH-d₄) δ 7.74 (d, J = 2.7 Hz, 1H), 7.72-7.65 (m, 3H),7.35 (t, J = 9.3 Hz, 1H), 6.92-6.75 (m, 1H), 6.29 (dd, J = 16.7, 6.2 Hz,1H), 5.82 (dd, J = 10.6, 1.9 Hz, 1H), 4.62-3.98 (m, 6H), 3.77-3.42 (m,2H), 3.15 (t, J = 5.3 Hz, 3H), 1.43 (t, J = 6.8 Hz, 3H). 525.2  419a(2S)-4-(9-chloro- ¹H NMR (400 MHz, 532.1 10-(2,4- CDCl₃) δ 7.70 (d, J =30.4, difluorophenyl)-5- 1H), 7.23-7.18 (m, 1H), oxo-3,5-dihydro-7.06-6.97 (m, 2H), 5.82- 2H- 5.47 (m, 2H), 5.36-5.31 (m,[1,4]thiazino[2,3,4- 1H), 4.70-4.45 (m, 2H), ij]quinazolin-7-yl)-4.42-4.19 (m, 3H), 3.87- 1-(2- 3.69 (m, 1H), 3.52-3.43 (m,fluoroacryloyl)piper- 1H), 3.27-3.19 (m, 1H), azine-2-carbonitrile3.13-3.08 (m, 2H). 427 7-((S)-4-acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(2- chloro-4- fluorophenyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, MeOH-d₄) δ 7.68 (d, J = 5.5 Hz, 1H), 7.43 (dd, J = 8.7,2.4 Hz, 1H), 7.34-7.18 (m, 2H), 6.82 (dddd, J = 21.7, 16.5, 10.7, 2.5Hz, 1H), 6.28 (dd, J = 16.8, 5.4 Hz, 1H), 5.81 (dd, J = 10.6, 1.9 Hz,1H), 4.79 (br s, 1H), 4.60-3.97 (m, 6H), 3.76-3.41 (m, 2H), 3.26- 3.03(m, 3H), 1.43 (d, J = 6.7 Hz, 1.5H), 1.39 (d, J = 6.7 Hz, 1.5H).  519.1. 427a 7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(5-chloro-2,4- difluorophenyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CD₃OD) δ 6.78 (d, J = 6.8 Hz, 1H), 6.57 (t, J = 6.8 Hz,1H), 6.48-6.44 (t, J = 9.6 Hz, 1H), 5.92-5.87 (m, 1H), 5.40-5.34 (m,1H), 4.90 (d, J = 10.4 Hz, 1H), 3.88- 3.87(m, 1H), 3.67-3.09 (m, 5H),2.83-2.58(m, 2H), 2.31-2.28 (m, 3H), 0.52- 0.46 (m, 3H) 537.1 4417-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(5-fluoroquinolin-8-yl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, MeOH-d₄) δ 8.83 (dd, J = 4.3, 1.7 Hz, 1H), 8.65 (dd, J= 8.6, 1.7 Hz, 1H), 7.77- 7.60 (m, 3H), 7.49 (t, J = 9.6 Hz, 1H), 6.84(ddd, J = 22.8, 16.8, 10.5 Hz, 1H), 6.29 (dd, J = 16.8, 6.7 Hz, 1H),5.82 (dd, J = 10.5, 1.9 Hz, 1H), 4.82 (br s, 1H), 4.63-3.99 (m, 5H),3.79- 3.41 (m, 2H), 3.24-2.95 (m, 3H), 1.46 (d, J = 6.8 Hz, 1.5H), 1.38(d, J = 6.7 Hz, 1.5H) 536.2 410 (S)-7-((S)-4- acryloyl-2-methylpiperazin-1- yl)-9-chloro-3((4- ethylpiperazin-1-yl)methyl)-10-(4- fluorophenyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.47 (s, 1H), 7.23-7.20 (m, 4H), 6.65- 6.50(m, 1H), 6.36 (d, J = 16.8 Hz, 1H), 5.77 (d, J = 10.8 Hz, 1H), 5.39-5.30(m, 1H), 4.74-4.64 (m, 1H), 4.57-4.16 (m, 2H), 3.98- 3.78 (m, 1H),3.64-3.36 (m, 3H), 3.09-2.95 (m, 2H), 2.84-2.73 (m, 3H), 2.55- 2.35 (m,9H), 1.47-1.43 (m, 3H), 1.08-1.04 (m, 3H),. 611.2 411 (3S)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10- (2,4- difluorophenyl)-3-((4-methylpiperazin- 1-yl)methyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.24-7.18 (m, 1H), 7.06- 6.95(m, 2H), 6.66-6.50 (m, 1H), 6.36 (d, J = 16.8 Hz, 1H), 5.77 (d, J = 10.4Hz, 1H), 5.41-5.28 (m, 1H), 4.73-4.19 (m, 3H), 3.98- 3.78 (m, 1H),3.60-3.39 (m, 3H), 3.08-3.00 (m, 2H), 2.84-2.76 (m, 3H), 2.55- 2.39 (m,7H), 2.55 (m, 3H), 1.48-1.43 (m, 3H). 615.2 412 (3S)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(5- chloro-2,4-difluorophenyl)-3- ((4-ethylpiperazin-1- yl)methyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.30 (t, J = 7.6 Hz, 1H),7.12-7.07 (m, 1H), 6.66-6.52 (m, 1H), 6.39-6.35 (m, 1H), 5.78 (d, J = 10.8Hz, 1H), 5.40-5.34 (m, 1H), 4.71- 4.64 (m, 1H), 4.54-4.32 (m, 1.5H),4.20-4.17 (m, 0.5H), 3.98-3.96 (m, 0.5H), 3.82- 3.79 (m, 0.5H),3.59-3.57 (m, 1.5H), 3.45-3.42 (m, 1.5H), 3.05-3.02 (m, 2H), 2.84-2.74(m, 3H), 2.57- 2.36 (m, 9H), 1.48-1.44 (m, 3H), 1.09-1.05 (m, 3H). 663.2413 (3S)-7-((S)-4- acryloyl-2- methylpiperazin-1- yl)-9-chloro-10- (2,4-difluorophenyl)-3- ((1-ethylpiperidin-4- yl)methyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.49 (s, 1H), 7.24-7.18 (m, 1H), 7.07- 6.96(m, 2H), 6.61-6.52 (m, 1H), 5.79-5.76 (d, J = 11.2 Hz, 1H), 5.46 (s,1H), 4.75- 4.15 (m, 4H), 3.58-3.46 (m, 1H), 3.13-3.07(m, 2H), 3.02-2.89(m, 3H), 2.39- 2.37(dd, J = 2.0 Hz, 2H), 1.93-1.88 (m, 2H), 1.79- 1.66(m, 3H), 1.46-1.42(d, J = 14.4 Hz, 2H), 1.36-1.32 (m, 2H), 1.09-1.05 (m,3H). 628.3 414 (3S)-7-((S)-4- acryloyl-2- methylpiperazin-1-yl)-9-chloro-3-((1- (2,2- difluoroethyl)piperidin- 4-yl)methyl)-10-(2,4- difluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.50 (s, 1H), 7.26-7.24(m, 1H), 7.07- 6.97 (m,2H), 6.67-6.51 (m, 1H), 6.35 (d, J = 23.6 Hz, 1H), 6.01-5.70 (m, 2H),5.51-5.37 (m, 1H), 4.78- 4.64 (m, 1H), 4.59-4.16 (m, 2H), 4.03-3.76 (m,1H), 3.64-3.42 (m, 2H), 3.15- 3.03 (m, 2H), 2.98-2.87 (m, 3H), 2.74-2.63(m, 2H), 2.22-2.08 (m, 2H), 1.77- 1.71 (m, 4H), 1.48-1.28 (m, 6H). 664.3415 (3S)-7-((S)-4- acryloyl-2- methylpiperazin-1- yl)-9-chloro-10- (2,4-difluorophenyl)-3- ((1-(oxetan-3- yl)piperidin-4- yl)methyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.50 (s, 1H), 7.24-7.20 (m, 1H), 7.07- 6.97(m, 2H), 6.61-6.51 (m, 1H), 6.35 (d, J = 27.2 Hz, 1H), 5.79 (d, J = 18.4Hz, 1H), 5.49-5.36 (m, 1H), 4.74-4.60 (m, 5H), 4.56- 4.15 (m, 2H),4.01-3.77 (m, 1H), 3.63-3.40 (m, 3H), 3.17-2.76 (m, 5H), 2.05- 1.86 (m,4H), 1.55-1.21 (m, 8H). 656.3 416 (3S)-7-((S)-4- acryloyl-2-methylpiperazin-1- yl)-9-chloro-3-((4- ethylpiperazin-1- yl)methyl)-10-(2,4,5- trifluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.12-7.07 (m, 2H), 6.66- 6.51(m, 1H), 6.37 (d, J = 16.8 Hz, 1H), 5.78 (d, J = 10.8 Hz, 1H), 5.40-5.34(m, 1H), 4.72-4.66 (m, 1H), 4.54-4.53 (m, 0.5H), 4.44- 4.34 (m, 1H),4.20-4.16 (m, 0.5H), 3.98-3.95 (m, 0.5H), 3.82-3.78 (m, 0.5H), 3.58-3.56 (m, 1.5H), 3.44-3.41 (m, 1.5H), 3.05-3.01 (m, 2H), 2.81-2.75 (m,3H), 2.57-2.40 (m, 8H), 1.45 (d, J = 19.6 Hz, 4H), 1.25 (s, 3H),1.10-1.06 (m, 3H). 647.3 421 (3S)-7-((S)-4- acryloyl-2-methylpiperazin-1- yl)-9-chloro-3-((1- (oxetan-3- yl)piperidin-4-yl)methyl)-10- (2,4,5- trifluorophenyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.50 (s, 1H), 7.15-7.05 (m, 2H), 6.62- 6.52(m, 1H), 6.37 (d, J = 16.8 Hz, 1H), 5.78 (d, J = 10.8 Hz, 1H), 5.48-5.41(m, 1H), 4.75-4.55 (m, 5.5H), 4.44-4.35 (m, 1H), 4.20- 4.17 (m, 0.5H),3.98-3.94 (m, 0.5H), 3.82-3.79 (m, 0.5H), 3.59-3.40 (m, 3H), 3.15-2.97(m, 3H), 2.71- 2.68 (m, 2H), 1.84-1.68 (m, 6H), 1.47-1.27 (m, 6H). 674.3422 (3S)-7-((S)-4- acryloyl-2- methylpiperazin-1- yl)-9-chloro-3((4-cyclopropylpiperazin- 1-yl)methyl)-10- (2,4- difluorophenyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.24-7.18 (m, 1H), 7.06- 6.95(m, 2H), 6.66-6.50 (m, 1H), 6.36 (d, J = 16.4 Hz, 1H), 5.77 (d, J = 10.8Hz, 1H), 5.40-5.31 (m, 1H), 4.73-4.68 (m, 1H), 4.55- 4.15 (m, 2H),3.99-3.77 (m, 1H), 3.59-3.41 (m, 3H), 3.08-3.00 (m, 2H), 2.83- 2.48 (m,10H), 1.48-1.43 (m, 3H), 1.26 (m, 1H), 0.42-0.39 (m, 4H). 641.3 423(3S)-7-((S)-4- acryloyl-2- methylpiperazin-1- yl)-9-chloro-10- (2,4-difluorophenyl)-3- ((1-methylpiperidin- 4-yl)methyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.50 (s, 1H), 7.24-7.18 (m, 1H), 7.08- 6.97(m, 2H), 6.68-6.32 (m, 2H), 5.80-5.36 (m, 2H), 4.78-4.66 (m, 1H), 4.62-4.15 (m, 2H), 4.00-3.76 (m, 1H), 3.62-3.42 (m, 2H), 3.16-2.83 (m, 6H),2.29 (s, 3H), 1.92-1.64 (m, 9H), 1.41-1.24 (m, 3H). 614.3 424(R)-7-((S)-4- acryloyl-2- methylpiperazin-1- yl)-9-chloro-3-((4-ethylpiperazin-1- yl)methyl)-10- (2,4,6- trifluorophenyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.50 (s, 1H), 6.84 (t, J = 7.2 Hz, 2H), 6.59-6.55 (m, 1H), 6.39-6.35 (m, 1H), 6.79-6.77 (d, J = 10.2 Hz, 1H),5.41-5.40 (m, 1H), 4.90-4.63 (m, 2H), 4.04- 4.01 (m, 2H), 3.7-3.65(m,2H), 3.46-3.43 (d, J = 12.8 Hz, 2H), 3.27-3.06 (m, 2H), 2.94-2.82 (m,3H), 2.55- 2.52 (m, 2H), 2.46-2.45 (m, 2H), 2.43-2.41 (m, 2H), 2.40-2.38(m, 3H), 1.37- 1.36 (d, J = 6.8 Hz, 3H), 1.10-1.06 (m, 3H). 647.3 425(S)-7-((S)-4- acryloyl-2- methylpiperazin-1- fluorophenyl)-3-((1-(oxetan-3- yl)piperidin-4- yl)methyl)-9- (trifluoromethyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.78 (s, 1H), 7.25-7.16 (m, 4H), 6.62- 6.53(m, 1H), 6.39-6.35 (m, 1H), 5.79 (d, J = 10.4 Hz, 1H), 5.40-5.39 (m,1H), 4.68-4.58 (m, 5H), 4.48- 4.25 (m, 2H), 3.98-3.80 (m, 1H), 3.63-3.38(m, 3H), 3.07-3.04 (m, 2H), 2.98- 2.94 (m, 1H), 2.70 (t, J = 12.4 Hz,2H), 1.84-1.69 (m, 6H), 1.52-1.40 (m, 4H), 1.39-1.26 (m, 2H). 672.3 426(3S)-7-((S)-4- acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(5-chloro-2,4- difluorophenyl)-3- ((1-(oxetan-3- yl)piperidin-4-yl)methyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.50 (s, 1H), 7.34-7.28 (m, 1H), 7.13- 7.07(m, 1H), 6.62-6.52 (m, 1H), 6.37 (d, J = 17.2 Hz, 1H), 5.78 (d, J = 10.8Hz, 1H), 5.49-5.43 (m, 1H), 4.73-4.54 (m, 5.5H), 4.47- 4.33 (m, 1H),4.21-4.17 (m, 0.5H), 3.99-3.96 (m, 0.5H), 3.83-3.80 (m, 0.5H), 3.58-3.49 (m, 1.5H), 3.49-3.39 (m, 1.5H), 3.16-2.97 (m, 3H), 2.74-2.70 (m,2H), 1.84-1.74 (m, 5H), 1.46- 1.32 (m, 7H). 690.3 428 (S)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-3-((1-(2,2- difluoroethyl)piperi-din-4-yl)methyl)-10- (4-fluorophenyl)-9- (trifluoromethyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.78 (s, 1H), 7.21-7.16 (m, 4H), 6.62- 6.54(m, 1H), 6.39 (d, J = 16.4 Hz, 1H), 6.00-5.70 (m, 2H), 5.39-5.37 (m,1H), 4.68-4.66 (m, 1H), 4.48- 4.39 (m, 1.5H), 4.29-4.25 (m, 0.5H),3.98-3.95 (m, 0.5H), 3.83-3.80 (m, 0.5H), 3.63-3.44 (m, 2H), 3.07 (d, J= 13.2 Hz, 2H), 2.97- 2.87 (m, 3H), 2.74-2.65 (m, 2H), 2.21-2.11 (m,2H), 1.74-1.67 (m, 4H), 1.52- 1.40 (m, 4H), 1.31-1.27 (m, 2H). 680.3 429(3S)-7-((S)-4- acryloyl-2- methylpiperazin-1- yl)-3-((1-(2,2-difluoroethyl)piperi- din-4-yl)methyl)-10- (2,4- difluorophenyl)-9-(trifluoromethyl)- 2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one1,1-dioxide

¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.43-7.26 (m, 1H), 7.02- 6.89(m, 2H), 6.56 (dd, J = 14.6 Hz, 1.6 Hz, 1H), 6.34 (d, J = 16.4 Hz, 1H),6.00- 5.70 (m, 2H), 5.08-5.04 (m, 1H), 5.04-4.30 (m, 3H), 4.14-3.77 (m,2H), 3.72- 3.43 (m, 3H), 3.33-3.07 (m, 1H), 2.96-2.89 (m, 2H), 2.74-2.65(m, 2H), 2.22- 2.07 (m, 3H), 1.78-1.62 (m, 4H), 1.45-1.25 (m, 5H) 730.3430 (S)-7-((S)-4- acryloyl-2- methylpiperazin-1- yl)-10-(4-fluorophenyl)-9- (trifluoromethyl)-3- ((3- (trifluoromethyl)-5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.21-7.20 (m, 4H), 6.61- 6.52(m, 1H), 6.39-6.35 (m, 1H), 5.79 (d, J = 10.4 Hz, 1H), 5.35-5.31 (brs,1H), 4.76-4.73 (m, 1H), 4.65- 4.56 (m, 1H), 4.43-4.33 (m, 2H), 4.17-3.96(m, 3H), 3.93-3.80 (m, 1H), 3.60- 3.42 (m, 4H), 3.20-3.06 (m, 4H),2.97-2.94 (m, 1H), 1.55-1.50 (m, 3H). 723.3 432 (3R)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10- (2,4- difluorophenyl)-3-(((1-ethylazetidin-3- yl)oxy)methyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, MeOH-d₄) δ 7.76 (s, 1H), 7.39-7.26 (m, 1H), 7.23- 7.07(m, 2H), 6.91-6.74 (m, 1H), 6.29 (dd, J = 16.6, 4.6 Hz, 1H), 5.81 (d, J= 10.6 Hz, 1H), 5.40-5.25 (m, 1H), 5.03-4.93 (m, 1H), 4.65-4.35 (m, 2H),4.33-4.00 (m, 3H), 3.98- 3.57 (m, 6H), 3.51-3.34 (m, 3H), 3.27-2.94 (m,3H), 1.40-1.26 (m, 3H), 1.25-1.11 (m, 3H) 616.2 4337′-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9′-chloro-10′- (2,4-difluorophenyl)- 3′H,5′H- spiro[cyclopropane- 1,2′- [1,4]thiazino[2,3,4-ij]quinazolin]-5′-one

¹H NMR (400 MHz, MeOH-d₄) δ 7.61 (d, J = 6.6 Hz, 1H), 7.18 (tdd, J =8.7, 6.3, 2.3 Hz, 1H), 7.09- 6.96 (m, 2H), 6.72 (dddd, J = 20.7, 16.7,10.5, 3.3 Hz, 1H), 6.19 (dd, J = 16.9, 6.2 Hz, 1H), 5.71 (dd, J = 10.6,2.0 Hz, 1H), 5.04 (d, J = 8.6 Hz, 1H), 4.58-4.40 (m, 1H), 4.36-3.87 (m,4H), 3.72-3.35 (m, 4H), 1.34 (d, J = 6.8 Hz, 1.5H), 1.29 (d, J = 6.7 Hz,1.5H), 1.08-0.99 (m, 2H), 0.93-0.76 (m, 2H) 529.2 434 (3S)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-10-(2,4- difluorophenyl)-3-((1-ethylpiperidin-4- yl)methyl)-9- (trifluoromethyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one 1,1-dioxide

¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.43-7.31 (m, 1H), 7.03- 6.89(m, 2H), 6.60-6.53 (m, 1H), 6.39 (dd, J = 1.2 Hz, 16.8 Hz, 1H), 5.81 (d,J = 10.4 Hz, 1H), 5.58-5.57 (m, 1H), 4.75-4.33 (m, 3H), 4.03-3.82 (m,1H), 3.69- 3.45 (m, 4H), 3.13-3.05 (m, 3H), 2.58-2.52 (m, 2H), 2.24-2.09(m, 3H), 1.92- 1.86 (m, 2H), 1.58-1.52 (m, 7H), 1.18 (t, J = 6.8 Hz,3H). 694.2 435 (3S)-7-((S)-4- acryloyl-2- methylpiperazin-1-yl)-10-(2,4- difluorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.21-7.16 (m, 1H), 7.04- 6.94(m, 2H), 6.66-6.51 (m, 1H), 6.37 (d, J = 16.8 Hz, 1H), 5.78(d, J = 10.4Hz, 1H), 5.40-5.38 (m, 1H), 4.74-4.29 (m, 3H), 3.99- 3.80 (m, 1H),3.67-3.34 (m, 8H), 3.11-2.99 (m, 2H), 1.55-1.50 (m, 3H). 581.1 436(3S)-7-((S)-4- acryloyl-2- methylpiperazin-1- yl)-10-(2,4-difluorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one 1,1-dioxide

¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.42-7.30 (m, 1H), 7.03- 6.88(m, 2H), 6.66-6.50 (m, 1H), 6.39 (dd, J = 1.6 Hz, 16.8 Hz, 1H), 5.80 (d,J = 10.4 Hz, 1H), 5.54-5.50 (m, 1H), 4.78-4.35 (m, 3H), 4.06-3.73 (m,4H), 3.61- 3.48 (m, 3H), 3.39 (d, J = 8.0 Hz, 3H), 3.10-3.03 (m, 1H),1.58-1.46 (m, 3H). 613.2 437 (3S)-7-((S)-4- acryloyl-2-methylpiperazin-1- yl)-10-(2,4- difluorophenyl)-3- ((tetrahydro-2H-pyran-4-yl)methyl)- 9-(trifluoromethyl)- 2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.79 (s, 1H), 7.23-7.15 (m, 1H), 7.05- 6.95(m, 2H), 6.62-6.55 (m, 1H), 6.39-6.35 (m, 1H), 5.79 (d, J = 10.4 Hz,1H), 5.45-5.42 (m, 1H), 4.70- 4.69 (m, 1H), 4.48-4.39(m, 1.5H),4.31-4.28 (m, 0.5H), 3.94 (t, J = 11.6 Hz, 2.5H), 3.83-3.81 (m, 0.5H),3.61- 3.45 (m, 2H), 3.42-3.32 (m, 2H), 3.14-3.97 (m, 3H), 1.80-1.72 (m,4H), 1.53- 1.35(m, 5H), 1.32-1.26(m, 1H). 635.2 438 (3S)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10- (2,4- difluorophenyl)-3-((tetrahydro-2H- pyran-4-yl)methyl)- 2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.50 (s, 1H), 7.24-7.19 (m, 1H), 7.08- 6.96(m, 2H), 6.62-6.54 (m, 1H), 6.39 (d, J = 16 Hz, 1H), 5.79 (d, J = 10.8Hz, 1H), 5.46 (s, 1H), 4.74-4.66 (m, 1H), 4.56 (s, 0.5H), 4.44-4.35 (m,1H), 4.20 (s, 0.5H), 3.96-3.91 (m, 2.5H), 3.91-3.79 (m, 0.5H), 3.58 (s,1.5H), 3.48-3.46 (m, 0.5H), 3.42-3.31 (m, 2H), 3.15-3.06(m, 2H), 2.99(d,J = 13.6 Hz, 1H), 1.77- 1.62(m, 5H), 1.47(d, J = 12.8 Hz, 4H),1.39-1.30(m, 1H). 601.2 443 (3S)-7-((2S,5R)-4- acryloyl-2,5-dimethylpiperazin- 1-yl)-3-((4-(2,2- difluoroethyl)pipera-zin-1-yl)methyl)-9- (trifluoromethyl)- 10-(2,4,5- trifluorophenyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.83 (s, 1H), 7.09-7.04 (m, 2H), 6.65- 6.50(m, 1H), 6.37 (t, J = 14.0 Hz, 1H), 6.01-5.70 (m, 2H), 5.37 (br, 1H),5.04 (br, 0.5H), 4.08-4.65 (m, 1H), 4.44-4.33(m, 1.5H), 4.08- 4.02 (m,0.5H), 3.77-3.63 (m, 2H), 3.42-3.01 (m, 3H), 2.75-2.56 (m, 11.5H), 1.48-1.37 (m, 6H). 731.3 444 (S)-7-((S)-4- acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(4- fluorophenyl)-3-((3- (trifluoromethyl)- 5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.51 (s, 1H), 7.23 (d, J = 7.2 Hz, 4H), 6.64-6.49 (m, 1H), 6.39-6.35 (m, 1H), 5.79-5.76 (m, 1H), 5.33-5.29 (m, 1H),4.73- 4.24 (m, 4H), 4.16-3.79 (m, 4H), 3.60-3.40 (m, 3H), 3.33-3.29 (m,1H), 3.17- 3.05 (m, 3H), 2.94-2.90 (m, 1H), 1.47 (d, J = 14.0 Hz, 3H).689.2 445 (S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-10- (4-fluorophenyl)-3- ((3- (trifluoromethyl)-5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, J = 9.6 Hz, 1H), 7.23 (d, J = 6.8 Hz,4H), 6.64-6.49 (m, 1H), 6.36 (t, J = 15.6 Hz, 1H), 5.77 (t, J = 7.6 Hz,1H), 5.42-5.40 (m, 1H), 5.00- 4.99 (m, 1H), 4.82-4.72(m, 1H), 4.38-3.99(m, 6H), 3.79-3.66 (m, 2H), 3.35- 3.19 (m, 3H), 3.10-3.07 (d, J = 11.6Hz, 2H), 2.93 (d, J = 12.4 Hz, 1H), 1.45-1.38 (m, 3H), 1.31-1.28 (m,3H). 703.3 446 (3S)-7-((S)-4- acryloyl-2- methylpiperazin-1-yl)-9-chloro-10-(5- chloro-2,4- difluorophenyl)-3- ((methoxymethoxy)methyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.49 (s, 1H), 7.32-7.28 (m, 1H), 7.12- 7.06 (m1H), 6.72-6.45 (m, 1H), 6.39-6.35 (m, 1H), 5.78 (d, J = 10.4 Hz, 1H),5.44 (brs, 1H), 4.98-4.97 (m, 1H), 4.69-4.62 (m, 2H), 4.15-3.95 (m, 1H),3.82- 3.76 (m, 3H), 3.40-3.35 (m, 4H), 3.35-2.78 (m, 2H), 1.65-1.63 (m,3H), 1.35 (d, J = 6.8 Hz, 3H). 611.1 447 (3S)-7-((S)-4- acryloyl-2-methylpiperazin-1- yl)-9-chloro-10-(5- chloro-2,4- difluorophenyl)-3-((3- (trifluoromethyl)- 5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.51 (s, 1H), 7.32-7.29 (m, 1H), 7.13- 7.09(m, 1H), 6.61-6.52 (m, 1H), 6.39-6.35 (m, 1H), 5.79 (d, J = 10.4 Hz,1H), 5.37-5.36 (m, 1H), 4.69- 4.67 (m, 1H), 4.57-4.31 (m, 3H), 4.27-3.95(m, 4H), 3.60-3.35 (m, 4H), 3.19- 2.90 (m, 5H), 1.47-1.41 (m, 3H). 741.2448 (3S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-10- (5-chloro-2,4- difluorophenyl)-3- ((3-(trifluoromethyl)- 5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)methyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.59-7.53 (m, 1H), 7.33-7.28 (m, 1H),7.13-7.08 (m, 1H), 6.61- 6.48 (m, 1H), 6.40-6.32 (m, 1H), 5.79-5.75 (m,1H), 5.54-5.38 (m, 1H), 5.03- 4.96 (m, 0.5 H), 4.80-4.70 (m, 1H),4.38-4.09 (m, 2.5H), 4.07-3.96 (m, 3.5H), 3.71-3.65 (m, 2H), 3.30- 3.08(m, 5.5H), 2.96-2.91 (m, 1H), 1.46-1.38 (m, 3H), 1.32-1.25 (m, 3H).755.2 449 (3S)-3-(2-oxa-7- azaspiro[3.5]nonan- 7-ylmethyl)-7-((2S,5R)-4-acryloyl- 2,5- dimethylpiperazin- 1-yl)-9-chloro-10-(5-chloro-2,4- difluorophenyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.52 (s, 1H), 7.29-7.27 (m, 1H), 7.12- 7.06(m, 1H), 6.65-6.50 (m, 1H), 6.37 (t, J = 14.8 Hz, 1H), 5.79-5.75 (m,1H), 5.42 (s, 1H), 5.00-4.68 (m, 2H), 4.38-3.97 (m, 6H), 3.78-3.65 (m,2H), 3.36- 3.35 (m, 1H), 3.05-3.00 (m, 1H), 2.71-2.37 (m, 6H), 1.81 (br,4H), 1.39-1.25 (m, 6H). 690.2 455 (S)-8-(4-acryloyl-2-methylpiperazin-1- yl)-10- (trifluoromethyl)- 11-(2,4,6-trifluorophenyl)-3,4- dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6- one

¹H NMR (400 MHz, MeOH-d₄) δ 7.64 (s, 1H), 6.96 (t, J = 8.5 Hz, 2H), 6.72(ddd, J = 21.6, 16.6, 10.6 Hz, 1H), 6.18 (dd, J = 16.8, 6.3 Hz, 1H),5.71 (dd, J = 10.6, 2.0 Hz, 1H), 5.13- 4.99 (m, 2H), 4.60-4.48 (m, 4H),4.33-3.84 (m, 2H), 3.63-3.45 (m, 3H), 2.18-2.03 (m, 2H), 1.31 (d, J =6.8 Hz, 3H) 535.2 456 (3S)-3-(2-oxa-7- azaspiro[3.5]nonan-7-ylmethyl)-7((S)- 4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(5-chloro-2,4- difluorophenyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.47 (s, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.12-7.06 (m, 1H), 6.65-6.50 (m, 1H), 6.39-6.34 (m, 1H), 5.77 (d, J = 11.2Hz, 1H), 5.36-5.26 (m, 1H), 4.72- 4.64 (m, 1H), 4.57-4.49 (m, 0.5H),4.44-4.38 (m, 5H), 4.23-4.18 (m, 0.5H), 3.99- 3.78 (m, 1H), 3.75-3.41(m, 3H), 3.06-2.99 (m, 2H), 2.79-2.59 (m, 3H), 2.48- 2.36 (m, 3H),1.86-1.80 (m, 4H), 1.48-1.44 (m, 3H). 676.3 457 (3S)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(5- chloro-2,4-difluorophenyl)-3- ((4-(2,2- difluoroethyl)pipera- zin-1-yl)methyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.31-7.28 (m, 1H), 7.10 (q, J =8.4 Hz, 1H), 6.62-6,51 (m, 1H), 6.37 (d, J = 16.8 Hz, 1H), 6.00-5.72 (m,2H), 5.40-5.29 (m, 1H), 4.80- 4.70 (m, 1H), 4.64-4.61(m, 0.5H),4.51-4.29 (m, 1H), 4.23-3.16 (m, 0.5H), 4.04- 3.37 (m, 5H), 3.18-2.92(m, 3H), 2.76-2.44 (m, 10H), 1.49-1.44 (m, 3H). 699.2 458 (3S)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(5- chloro-2,4-difluorophenyl)-3- ((4- cyclopropylpiperazin- 1-yl)methyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.33-7.28 (m, 1H), 7.13- 7.06(m, 1H), 6.67-6.48 (m, 1H), 6.37 (d, J = 20.4 Hz, 1H), 5.77 (d, J = 17.6Hz, 1H), 5.43-5.29 (m, 1H), 4.75-4.67 (m, 1H), 4.57- 3.94 (m, 3H),3.82-3.40 (m, 4H), 3.10-3.01 (m, 2H), 2.84-2.49 (m, 9H), 1.50- 1.42 (m,3H), 1.27-1.26 (m, 1H), 0.46-0.44 (m, 4H). 675.2 459 (3S)-7-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-9-chloro-3-((3-(trifluoromethyl)- 5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)methyl)-10- (2,4,5- trifluorophenyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.59-7.53 (m, 1H), 7.16-7.03 (m, 2H),6.61-6.48 (m, 1H), 6.40- 6.32 (m, 1H), 5.79-5.75 (m, 1H), 5.53-5.43(brs, 1H), 5.04-4.96 (brs, 0.5 H), 4.83-4.71 (m, 1H), 4.36- 4.03 (m,6H), 3.75-3.66 (m, 2H), 3.33-3.03 (m, 5.5H), 2.94-2.88 (m, 1H), 1.46-1.36 (m, 3H), 1.32-1.26 (m, 3H) 739.2 460 3S)-3-(2-oxa-7-azaspiro[3.5]nonan- 7-ylmethyl)-7- ((2S,5R)-4-acryloyl- 2,5-dimethylpiperazin- 1-yl)-9-chloro-10- (2,4,5- trifluorophenyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.53 (s, 1H), 7.14-7.04 (m, 2H), 6.66- 6.50(m, 1H), 6.37 (t, J = 14.4 Hz, 1H), 5.77 (t, J = 7.6 Hz, 1H), 5.42-5.37(m, 1H), 5.00-4.82 (m, 1H), 5.70-5.68 (m, 0.5H), 4.38- 4.31 (m, 5H),4.21-3.96 (m, 1H), 3.81-3.65 (m, 2.5H), 3.37-3.30 (m, 1H), 3.04- 3.01(m, 1H), 2.73-2.35 (m, 6H), 1.84-1.79 (m, 4H), 1.39-1.30 (m, 6H). 674.3461 (3S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-10- (5-chloro-2,4- difluorophenyl)-3- ((1-(2,2-difluoroethyl)piperi- din-4-yl)methyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.52-7.51 (m, 1H), 7.34-7.30 (m, 1H),7.12-7.07 (m, 1H), 6.61- 6.51 (m, 1H), 6.37 (t, J = 13.6 Hz, 1H),5.99-5.70 (m, 1H), 5.78-5.75 (m, 1H), 5.53-5.50 (m, 1H), 4.97- 4.90 (m,1.5H), 4.75-4.73 (m, 0.5H), 4.38-4.29 (m, 1H), 4.20-4.17 (m, 0.5H),3.98-3.81 (m, 2H), 3.74- 3.65 (m, 1H), 3.40-3.38 (m, 0.5H), 3.18-3.12(m, 1H), 2.97-2.88 (m, 3H), 2.72- 2.63 (m, 2H), 2.18-2.08 (m, 2H),1.85-1.83 (m, 1H), 1.71-1.65 (m, 2H), 1.40- 1.38 (m, 5H), 1.30-1.25 (m,4H). 714.2 462 (S)-3-(2-oxa-7- azaspiro[3.5]nonan- 7-ylmethyl)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(4- fluorophenyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.23-7.18 (m, 4H), 6.62- 6.52(m, 1H), 6.36 (d, J = 18.0 Hz, 1H), 5.77 (d, J = 10.8 Hz, 1H), 5.29-5.27(m, 1H), 4.74-4.70 (m, 1H), 4.64 (m, 0.5H), 4.54-4.38 (m, 5H), 4.21-4.19(m, 0.5H), 3.96-3.95 (m, 0.5H), 3.81-3.77 (m, 0.5H), 3.62- 3.49 (m, 2H),3.37-3.36 (m, 1H), 3.12-3.07 (m, 1H), 3.00-2.94 (m, 1H), 2.79- 2.73 (m,1H), 2.65-2.55 (m, 2H), 2.49-2.47 (m, 1H), 2.43-2.35 (m, 2H), 1.88- 1.75(m, 4H), 1.48-1.44 (m, 3H). 624.3 463 (3S)-7-((S)-4- acryloyl-2-methylpiperazin-1- yl)-9-chloro-3-((3- (trifluoromethyl)- 5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methyl)-10- (2,4,5-trifluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.51 (s, 1H), 7.15-7.04 (m, 2H), 6.63- 6.50(m, 1H), 6.39-6.35 (m, 1H), 5.78 (d, J = 10.8 Hz, 1H), 5.37-5.35 (m,1H), 4.70-4.68 (m, 1H), 4.55- 4.27 (m, 3H), 4.18-3.78 (m, 4H), 3.51-3.77(m, 4H), 3.18-2.90 (m, 5H), 1.52- 1.44 (m, 3H). 725.2 466 (3R)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-3- ((methoxymethoxy)methyl)-10-(2,4,5- trifluorophenyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.52-7.50 (m, 1H), 7.15-7.06 (m, 2H),6.59-6.53 (m, 1H), 6.38 (d, J = 16.4 Hz, 1H), 5.78 (d, J = 10.0 Hz, 1H),5.49-5.45 (m, 1H), 4.97-4.94 (m, 0.5H), 4.65 (dt, J = 16.0 Hz, 8.0 Hz,3H), 4.52-4.46 (m, 0.5H), 4.10-3.96 (m, 1.5H), 3.82-3.60 (m, 4.5H),3.45-3.35 (m, 4H), 3.26- 3.19 (m, 0.5H), 3.19-3.10 (m, 1H), 2.92-2.87(m, 0.5H), 1.35 (d, J = 6.4 Hz, 3H). 595.1 467 (3S)-7-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-9-chloro-10- (5-chloro-2,4-difluorophenyl)-3- ((1- cyclopropylpiperidin- 4-yl)methyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.51-7.50 (m, 1H), 7.34-7.28 (m, 1H),7.12-7.07 (m, 1H), 6.66- 6.51 (m, 1H), 6.37 (t, J = 14.4 Hz, 1H), 5.78(d, J = 10.0 Hz, 1H), 5.51-5.49 (m, 1H), 4.96-4.92 (m, 1H), 4.76-4.75(m, 0.5H), 4.37- 4.30 (m, 0.7H), 4.22-4.13 (m, 0.5H), 3.98-3.65 (m, 3H),3.42-3.37 (m, 0.3H), 3.16-3.12 (m, 1H), 2.98- 2.96 (m, 3H), 2.14-2.04(m, 2H), 1.84-1.82(m, 1H), 1.51-1.49 (m, 2H), 1.39 (d, J = 6.4 Hz, 6H),1.29-1.25 (m, 5H), 0.41-0.37 (m, 4H). 688.2 468 (3S)-7-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-9-chloro-10- (2,4-difluorophenyl)-3- ((3- (trifluoromethyl)- 5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.59-7.56 (m, 1H), 7.26-7.18 (m, 1H),7.08-6.98 (m, 2H), 6.64- 6.49 (m, 1H), 6.40-6.33 (m, 1H), 5.79-5.75 (m,1H), 5.44-5.42 (m, 1H), 5.02- 5.00 (m, 0.5H), 4.80-4.72 (m, 1H),4.39-3.96 (m, 6.5H), 3.75-3.65 (m, 2H), 3.30-3.26 (m, 2H), 3.18- 3.11(m, 2H), 3.08-3.02 (m, 1H), 2.92-2.89 (m, 1H), 1.46-1.43 (m, 3H), 1.33-1.27 (m, 3H). 721.3 469 (3S)-3-(2-oxa-7- azaspiro[3.5]nonan-7-ylmethyl)-7-((S)- 4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(2,4,5- trifluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

¹H NMR (400 MHz, CDCl₃) δ 7.47 (s, 1H), 7.14-7.04 (m, 2H), 6.61- 6.51(m, 1H), 6.39-6.34 (m, 1H), 5.77 (d, J = 11.6 Hz, 1H), 5.37-5.26 (m,1H), 4.96-4.94 (m, 1H), 4.56- 4.34 (m, 5.5H), 4.21-4.19 (m, 0.5H),3.97-3.93 (m, 0.5H), 3.81-3.78 (m, 0.5H), 3.62-3.41 (m, 3H), 3.05- 2.99(m, 2H), 2.78-2.70 (m, 1H), 2.60-2.59 (m, 2H), 2.48-2.35 (m, 3H), 1.86-1.80 (m, 4H), 1.48-1.44 (m, 3H). 660.2 470 (3R)-7-((S)-4- acryloyl-2-methylpiperazin-1- yl)-10-(5-chloro- 2,4-difluorophenyl)- 3-((methoxymethoxy) methyl)-9- (trifluoromethyl)- 2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.78-7.75 (m, 1H), 7.29-7.26 (m, 1H), 7.109-7.04 (m, 1H), 6.59- 6.53 (m, 1H), 6.40-6.36 (m, 1H), 5.79 (dd, J =10.0 Hz, 1.2 Hz, 1H), 5.52-5.44 (m, 1H), 5.05-4.95 (m, 0.5H), 4.99-4.62(m, 3H), 4.11- 4.00 (m, 1H), 3.85-3.68 (m, 3H), 3.67-3.45 (m, 1H),3.41-3.05 (m, 5H), 3.10- 3.05 (m, 1H), 2.90-2.86 (m, 0.5H), 1.38 (d, J =6.8 Hz, 3H). 645.1 471 (3R)-7-((S)-4- acryloyl-2- methylpiperazin-1-yl)-3- ((methoxymethoxy) methyl)-9- (trifluoromethyl)- 10-(2,4,5-trifluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.76 (s, 1H), 7.12-7.03 (m, 2H), 6.59- 6.53(m, 1H), 6.38 (dd, J = 16.8, 1.6 Hz, 1H), 5.79 (dd, J = 10.4, 1.2 Hz,1H), 5.79 (brs, 1H), 5.00 (brs, 0.5H), 4.81-4.62 (m, 3H), 4.50- 4.47 (m,0.5H), 4.14-4.00 (m, 1.5H), 3.89-3.64 (m, 4.5H), 3.42-3.35 (m, 4.5H),3.10-3.04 (m, 1H), 2.92- 2.86 (m, 0.5H), 1.38 (d, J = 6.8 Hz, 3H). 629.2472 (3S)-3-(2-oxa-7- azaspiro[3.5]nonan- 7-ylmethyl)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10- (2,4-difluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.21 (q, J = 27.6 Hz, 1H), 7.07-6.95 (m, 2H), 6.66-6.50 (m, 1H), 6.37 (d, J = 18.4 Hz, 1H), 5.77 (d, J =10.0 Hz, 1H), 5.38-5.26 (m, 1H), 4.73-4.69 (m, 1H), 4.62- 4.59 (m,0.5H), 4.38-4.35 (m, 5H), 4.21-4.17 (m, 0.5H), 3.98-3.78 (m, 1H),3.65-3.54 (m, 2H), 3.50- 3.03 (m, 4H), 2.81-2.67 (m, 1H), 2.59-2.50 (m,2H), 2.48-2.30 (m, 2H), 2.00- 1.71 (m, 4H), 1.49-1.39 (m, 3H). 642.2 473(S)-3-(2-oxa-7- azaspiro[3.5]nonan- 7-ylmethyl)-7- ((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-9-chloro-10- (4-fluorophenyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.53 (s, 1H), 7.23-7.19 (m, 4H), 6.66- 6.50(m, 1H), 6.37 (t, J = 14.4, 1H), 5.77 (t, J = 8.4 Hz, 1H), 5.44-5.29 (m,1H), 4.98-4.66 (m, 2H), 4.55- 4.46 (m, 1H), 4.38 (s, 4H), 4.32-4.19 (m,1H), 3.99 (d, J = 13.6 Hz, 1H), 3.81-3.60 (m, 2H), 3.38-3.25 (m, 1H),2.96 (d, J = 12.4 Hz, 1H), 2.76-2.37 (m, 6H), 1.84- 1.80 (m, 3H),1.39-1.26 (m, 6H). 638.3 474 (3S)-7-((S)-4- acryloyl-2-methylpiperazin-1- yl)-9-chloro-10-(5- fluoroquinolin-8-yl)-3-(methoxymethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, MeOH-d₄) δ 8.83 (dd, J = 4.3, 1.7 Hz, 1H), 8.66 (dd, J= 8.5, 1.8 Hz, 1H), 7.72 (d, J = 2.9 Hz, 1H), 7.66 (td, J = 8.6, 5.1 Hz,2H), 7.56- 7.47 (m, 1H), 6.83 (ddd, J = 27.5, 16.7, 10.5 Hz, 1H), 6.29(dd, J = 16.8, 7.5 Hz, 1H), 5.82 (d, J = 9.8 Hz, 1H), 5.41-5.25 (m, 1H),4.86-4.69 (m, 2H), 4.64- 4.32 (m, 2H), 4.24-3.97 (m, 1H), 3.76-3.46 (m,4H), 3.33 (s, 3H), 3.27- 3.06 (m, 3H), 1.48 (dd, J = 7.0, 3.3 Hz, 3H)580.2 475 (3S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-3-((1- cyclopropylpiperidin- 4-yl)methyl)-10- (2,4,5-trifluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.51-7.50 (m, 1H), 7.14-7.07 (m, 2H),6.65-6.51 (m, 1H), 6.37 (t, J = 15.6 Hz, 1H), 5.78-5.75 (m, 1H),5.54-5.50 (m, 1H), 4.96-4.90 (m, 1H), 4.76- 4.74 (m, 0.5H), 4.38-4.30(m, 1H), 4.20 (d, J = 10.4 Hz, 0.5H), 3.98-3.94 (m, 0.6H), 3.85-3.81 (m,1H), 3.75-3.64 (m, 1H), 3.43- 3.38 (m, 0.4H), 3.17-3.12 (m, 1H),2.97-2.95 (m, 3H), 2.14-2.05 (m, 2H), 2.05- 1.82 (m, 1H), 1.51-1.50 (m,1H), 1.39-1.37 (m, 5H), 1.29-1.25 (m, 7H), 0.42- 0.37 (m, 4H). 672.3 476(3S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-3-((1- (2,2- difluoroethyl)piperi- din-4-yl)methyl)-10-(2,4,5- trifluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

¹H NMR (400 MHz, CDCl₃) δ 7.52 (s, 1H), 7.14-7.06 (m, 2H), 6.65- 6.51(m, (1H), 6.37 (t, J = 15.2 Hz, 1H), 5.98-5.70 (m, 2H), 5.53-5.51 (m,1H), 4.98-4.89 (m, 1H), 4.75- 4.73 (s, 0.5H), 4.37-4.29 (m, 1H),4.22-4.19 (m, 0.5H), 3.99-3.95 (m, 0.5H), 3.84 (d, J = 13.2 Hz, 1H),3.73-3.68 (m, 1H), 3.40- 3.36 (m, 0.5H), 3.17-3.12 (m, 1H), 2.97-2.88(m, 3H), 2.72-2.64 (m, 2H), 2.18- 2.08 (m, 2H), 1.85-1.81 (m, 1H),1.68-1.62 (m, 2H), 1.39 (d, J = 5.6 Hz, 6H), 1.27 (t, J = 7.6 Hz, 4H).696.2 477 (3S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-3-((1- (2,2- difluoroethyl)piperi- din-4-yl)methyl)-10-(2,4- difluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.52 (s, 1H), 7.24-7.20 (m, 1H), 7.05- 6.96(m, 2H), 6.65-6.51 (m, 1H), 6.37 (t, J = 13.6 Hz, 1H), 5.99-5.69 (m,2H), 5.52-5.50 (m, 1H), 4.98- 4.91 (m, 1H), 4.76-4.74 (m, 0.5H),4.38-4.30 (m, 1H), 4.23-4.19 (m, 0.5H), 4.00- 3.97 (m, 0.5H), 3.82-3.64(m, 2H), 3.41-3.37 (m, 0.5H), 3.15-3.11 (m, 1H), 2.94-2.87 (m, 3H), 2.68(t, J = 14.8 Hz, 2H), 2.18-2.08 (m, 2H), 1.86-1.83 (m, 1H), 1.70-1.66(m, 2H), 1.38- 1.36 (m, 6H), 1.28 (t, J = 7.6 Hz, 4H). 678.2 478(3S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-3-((1- cyclopropylpiperidin- 4-yl)methyl)-10- (2,4-difluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.51 (s, 1H), 7.26-7.20 (m, 1H), 7.04- 6.96(m, 2H), 6.65-6.51 (m, 1H), 6.36 (t, J = 15.2 Hz, 1H), 5.77 (d, J = 10.4Hz, 1H), 5.53-5.50 (m, 1H), 4.96-4.92 (m, 1H), 4.76- 4.74 (m, 0.5H),4.38-4.30 (m, 1H), 4.21-4.18 (m, 0.5H), 3.99-3.96 (m, 0.6H), 3.83-3.63(m, 2H), 3.42- 3.38 (m, 0.4H), 3.16-3.11 (m, 1H), 2.99-2.92 (m, 3H),2.12-2.04 (m, 2H), 1.84- 1.82 (m, 1H), 1.50-1.48 (m, 2H), 1.37-1.35 (m,5H), 1.29-1.26 (m, 6H), 0.41- 0.37 (m, 4H). 654.2 479 (3R)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10- (2,4- difluorophenyl)-3-((methoxymethoxy) methyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

¹H NMR (400 MHz, CDCl₃) δ 7.52-7.50 (m, 1H), 7.22 (m, 1H), 7.07- 6.95(m, 2H), 6.60-6.53 (m, 1H), 6.37 (dd, J = 16.8, 1.2 Hz, 1H), 5.77 (d, J= 10.4 Hz, 1H), 5.50-5.40 (m, 1H), 5.10-4.85 (m, 0.5H), 4.82- 4.62 (m,3H), 4.52-4.46 (m, 0.5H), 4.10-3.99 (m, 1.5H), 3.83-3.57 (m, 4H), 3.49-3.35 (m, 4.5H), 3.30-3.20 (m, 0.4H), 3.07 (d, J = 13.6 Hz, 1H),2.95-2.85 (m, 0.6H), 1.34 (d, J = 6.4 Hz, 3H). 577.2 480 (3S)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-3-((4- (2,2-difluoroethyl)pipera- zin-1-yl)methyl)-10- (2,4,5- trifluorophenyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.14-7.04 (m, 2H), 6.62- 6.51(m, 1H), 6.37 (d, J = 16.8 Hz, 1H), 6.00-5.72 (m, 2H), 5.34-5.33 (m,1H), 4.74-4.65 (m, 1H), 4.53- 4.36 (m, 1.5H), 4.21-4.16 (m, 0.5H),3.97-3.95 (m, 0.5H), 3.81-3.77 (m, 0.5H), 3.57-3.50 (m, 1.5H), 3.42 (d,J = 13.2 Hz ,1.5H), 3.04-3.01 (m, 2H), 2.87- 2.67 (m, 5H), 2.55-2.53 (m,7H), 1.48-1.44 (m, 3H). 683.2 481 (S)-7-((2S,5R)-4- acryloyl-2,5-dimethylpiperazin- 1-yl)-3-((1-(2,2- difluoroethyl)azetidin-3-yl)methyl)-10- (4-fluorophenyl)-9- (trifluoromethyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.84 (s, 1H), 7.26-7.25 (m, 1H), 7.21- 7.17(m, 3H), 6.67-6.51 (m, 1H), 6.38 (t, J = 15.6 Hz, 1H), 5.84-5.54 (m,2H), 5.27-5.26 (m, 1H), 5.06- 5.01 (m, 0.5H), 4.84-4.83 (m, 0.5H),4.71-4.70 (m, 0.5H), 4.42-4.32 (m, 1.5H), 4.06-4.03 (m, 0.5H), 3.80-3.67 (m, 2H), 3.59-3.52 (m, 2H), 3.33-3.29 (m, 0.5H), 3.06-2.97 (m, 3H),2.88- 2.84 (m, 1H), 2.79-2.70 (m, 2H), 2.61-2.53 (m, 1H), 2.06 (t, J =6.8 Hz, 1H), 1.47-1.38 (m, 6H). 666.3 482 (3S,10S)-3-((2-oxa- 7-azaspiro[3.5]nonan- 7-yl)methyl)-7-((S)- 4-acryloyl-2-methylpiperazin-1- yl)-9-chloro-10-(5- chloro-2,4- difluorophenyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.29 (t, J = 3.2 Hz, 1H), 7.10(t, J = 8.8 Hz, 1H), 6.66-6.51 (m, 1H), 6.37 (d, J = 18 Hz, 1H), 5.77(d, J = 10.8 Hz, 1H), 5.36-5.27 (m, 1H), 4.70-4.66 (m, 1H), 4.54- 4.19(m, 6H), 3.99-3.78 (m, 1H), 3.62-3.38 (m, 3H), 3.08-2.99 (m, 2H), 2.78-2.34 (m, 6H), 1.93-1.78 (m, 4H), 1.48-1.45 (m, 3H). 676.3 483(3S,10R)-3-((2-oxa- 7- azaspiro[3.5]nonan- 7-yl)methyl)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-10-(5- chloro-2,4-difluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.29 (t, J = 8.4 Hz, 1H), 7.09(t, J = 8.4 Hz, 1H), 6.66-6.50 (m, 1H), 6.37 (d, J = 16.4 Hz, 1H), 5.77(d, J = 10.4 Hz, 1H), 5.40-5.29 (m, 1H), 4.73-4.66 (m, 1H), 4.56- 4.52(m, 0.5H), 4.46-4.38 (m, 5H), 4.23-4.18 (m, 0.5H), 3.98-3.78 (m, 1H),3.63-3.42 (m, 3H), 3.05- 3.02 (m, 2H), 2.74-2.35 (m, 6H), 1.92-1.83 (m,4H), 1.50-1.42 (m, 3H). 676.3 484 (3S,10S)-3-((2-oxa- 7-azaspiro[3.5]nonan- 7-yl)methyl)-7- ((2S,5R)-4-acryloyl- 2,5-dimethylpiperazin- 1-yl)-9-chloro-10- (2,4,5- trifluorophenyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.52 (s, 1H), 7.14-7.05 (m, 2H), 6.66- 6.50(m, 1H), 6.37 (t, J = 14.4 Hz, 1H), 5.77 (t, J = 8.0 Hz, 1H), 5.42-5.34(m, 1H), 5.00-4.83 (m, 1H), 4.73-4.68 (m, 0.5H), 4.38- 4.23 (m, 5H),4.01-3.98 (m, 0.5H), 3.81-3.65 (m, 2H), 3.38-3.31 (m, 1.5H), 3.16- 3.00(m, 1.5H), 2.74-2.38 (m, 6H), 1.85-1.80 (m, 4H), 1.41-1.38 (m, 6H).674.3 485 (3S,10R)-3-((2-oxa- 7- azaspiro[3.5]nonan- 7-yl)methyl)-7-((2S,5R)-4-acryloyl- 2,5- dimethylpiperazin- 1-yl)-9-chloro-10- (2,4,5-trifluorophenyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.53 (s, 1H), 7.13-7.04 (m, 2H), 6.66- 6.50(m, 1H), 6.37 (t, J = 14.0 Hz, 1H), 5.77 (t, J = 6.8 Hz, 1H), 5.42-5.36(m, 1H), 4.99-4.84 (m, 1H), 4.75-4.70 (m, 0.5H), 4.37- 4.23 (m, 5H),4.01-3.98 (m, 0.5H), 3.81-3.65 (m, 2H), 3.39-3.31 (m, 1.5H), 3.16- 3.01(m, 1.5H), 2.72-2.35 (m, 6H), 1.85-1.81 (m, 4H), 1.41-1.32 (m, 6H).674.3 491 (3S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin- 1-yl)-3-(methoxymethyl)-9- (trifluoromethyl)- 10-(2,4,5- trifluorophenyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.86-7.83 (m, 1H), 7.11-7.02 (m, 2H),6.66-6.50 (m, 1H), 6.37 (t, J = 14.4 Hz, 1H), 5.78 (t, J = 8.4 Hz, 1H),5.43-5.39 (m, 1H), 5.07-5.04 (m, 0.6H), 4.80-4.66 (m, 1H), 4.43-4.33 (m,1.4H), 4.13- 4.07 (m, 0.5H), 3.75-3.62 (m, 4H), 3.40-3.34 (m, 4H),3.26-3.21 (m, 0.5H), 3.05- 3.02 (m, 1H), 1.49-1.41 (m, 6H). 613.2 492(3S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin- 1-yl)-10-(5-chloro-2,4-difluorophenyl)- 3-(methoxymethyl)- 9-(trifluoromethyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.86-7.83 (m, 1H), 7.30-7.28 (m, 1H), 7.07 (t,J = 8.8 Hz, 1H), 6.66-6.50 (m, 1H), 6.37 (t, J = 14.4 Hz, 1H), 5.78 (t,J = 8.8 Hz , 1H), 5.45-5.41 (m, 1H), 5.08-5.04 (m, 0.6H), 4.79-4.67 (m,1H), 4.44-4.33 (m, 1.4H), 4.12- 4.06 (m, 0.5H), 3.72-3.62 (m, 4H),3.41-3.34 (m, 4H), 3.27-3.20 (m, 0.5H), 3.05- 3.02 (m, 1H), 1.49-1.40(m, 6H). 629.2 493 (3S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-10-(2,4- difluorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.86-7.83 (m, 1H), 7.22-7.13 (m, 1H),7.05-6.94 (m, 2H), 6.67- 6.50 (m, 1H), 6.37 (t, J = 14.8 Hz, 1H), 5.77(t, J = 8.8 Hz , 1H), 5.45-5.39 (m, 1H), 5.07-5.05 (m, 0.6H), 4.81-4.68(m, 1H), 4.44- 4.34 (m, 1.4H), 4.15-4.07 (m, 0.5H), 3.76-3.60 (m, 4H),3.42-3.26 (m, 4.5H), 3.05-3.00 (m, 1H), 1.49- 1.41 (m, 6H). 595.2 494(3S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin- 1-yl)-9-chloro-10-(2,4- difluorophenyl)-3- (methoxymethyl)- 2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.56 (s, 1H), 7.24-7.17 (m, 1H), 7.07- 6.98(m, 2H), 6.67-6.52 (m, 1H), 6.37 (t, J = 14.4 Hz, 1H), 5.79-5.75 (m,1H), 5.52-5.46 (m, 1H), 5.10- 5.02 (m, 0.6H), 4.84-4.71 (m, 1H),4.40-4.32 (m, 1.4H), 4.08-4.02 (m, 0.6H), 3.79-3.55 (m, 4H), 3.49 (d, J= 6.4 Hz, 3H), 3.32-3.29 (m, 1.4H), 3.05-3.02 (m, 1H), 1.44-1.34 (m,6H). 561.2 495 (3S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-10- (5-chloro-2,4- difluorophenyl)-3- ((4-(2,2-difluoroethyl)pipera- zin-1-yl)methyl)- 2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.52 (s, 1H), 7.31-7.28 (m, 1H), 7.12- 7.06(m, 1H), 6.66-6.50 (m, 1H), 6.37 (t, J = 16 Hz, 1H), 6.00-5.70 (m, 2H),5.43-5.36 (m, 1H), 4.99- 4.69 (m, 1.5H), 4.40-4.21 (m, 1.5H), 3.98 (d, J= 14 Hz, 0.5H), 3.82-3.65 (m, 2H), 3.35-5.33 (m, 1.5H), 3.05-3.02 (m,1H), 2.74- 2.67 (m, 5H), 2.57-2.54 (m, 7H), 1.39-1.37 (m, 3H), 1.35-1.26(m, 3H). 713.2 496 (3S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-10- (5-chloro-2,4- difluorophenyl)-3- (methoxymethyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.57-7.52 (m, 1H), 7.33-7.29 (m, 1H),7.12-7.07 (m, 1H), 6.64- 6.50 (m, 1H), 6.41-6.33 (m, 1H), 5.80-5.75 (m,1H), 5.47 (s, 1H), 5.01 (s, 0.5H), 4.84(s, 0.5H), 4.70 (s, 0.5H),4.38-4.30 (m, 1H), 4.06-4.03 (m, 0.5H), 3.80- 3.57 (m, 4H), 3.41-3.37(d, J = 16.0 Hz, 3H), 3.34- 3.31 (m, 1H), 3.06-3.03 (m, 1H),1.43-1.34(m,6H).1.25(s, 1H) 595.1 497 (S)-7-((2S,5R)-4- acryloyl-2,5-dimethylpiperazin- 1-yl)-10-(4- fluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)- 2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.85-7.83 (d, J = 8.0 Hz, 1H), 7.24-7.15 (m,4H), 6.67-6.51 (m, 1H), 6.41-6.34 (m, 1H), 5.80- 5.76 (m, 1H), 5.41-5.40(m, 1H), 5.06 (s, 0.5H), 4.81- 4.79 (m, 0.5H), 4.46-4.34 (m, 1H),4.13-4.09 (d, J = 16.0 Hz, 0.5H), 3.72-3.62 (m, 4H), 3.40 (s, 3H),3.32-3.21 (m, 2H), 2.99- 2.97 (d, J = 8.0 Hz, 0.5H),1.50-1.42 (m, 6H),1.25 (m, 1H). 577.2 498 (3S)-7-((2S,5R)-4- acryloyl-2,5-dimethylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-3- ((2-methoxyethoxy)meth- yl)-9- (trifluoromethyl)- 2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.87-7.83 (m, 1H), 7.19-7.15 (m, 1H),7.03-6.95 (m, 2H), 6.67- 6.51 (m, 1H), 6.37 (t, J = 14.4 Hz, 1H), 5.78(t, J = 9.2 Hz, 1H), 5.50-5.36 (m, 1H), 5.14-5.00 (m, 0.6H), 4.78-4.66(m, 1H), 4.45- 4.41(m, 1H), 4.41-4.34 (m, 0.4H), 4.16-4.08 (m, 0.6H),3.78-3.63 (m, 6H), 3.52 (t, J = 4.8 Hz, 2H), 3.41-3.38 (m, 1H), 3.35 (s,3H), 3.26- 3.22 (m, 0.4H), 3.05-2.95 (m, 1H), 1.50-1.44 (m, 6H). 639.3499 (3S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-10- (5-chloro-2,4- difluorophenyl)-3- ((4-cyclopropylpiperazin- 1-yl)methyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.52 (s, 1H), 7.32-7.30 (m, 1H), 7.13- 7.05(m, 1H), 6.67-6.489 (m, 1H), 6.37 (t, J = 13.6 Hz, 1H), 5.79-5.75 (m,1H), 5.48-5.37 (m, 1H), 5.01- 4.67 (m, 2H), 4.42-3.95 (m, 2H), 3.84-3.66(m, 2H), 3.40-3.31 (m, 1H), 3.10- 3.08 (m, 1H), 2.82-2.48 (m, 10H),1.46-1.24 (m, 7H), 0.57-0.40 (m, 4H). 689.3 500 (3S)-3-((1S,4S)-2-oxa-5- azabicyclo[2.2.1]hep- tan-5-ylmethyl)-7- ((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-9-chloro-10- (5-chloro-2,4-difluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.54-7.52 (m, 1H), 7.32-7.25 (m, 1H),7.12-7.06 (m, 1H), 6.66- 6.50 (m, 1H), 6.41-6.33 (m, 1H), 5.79-5.75 (m,1H), 5.28-5.24 (m, 1H), 5.01- 4.70 (m, 2H), 4.40-4.26 (m, 2H), 4.02-3.90(m, 2H), 3.69-3.55 (m, 4H), 3.46- 3.29 (m, 1H), 3.03-2.86 (m, 5H),1.77-1.65 (m, 2H), 1.52-1.33 (m, 6H). 662.3 501 (3S)-7-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-9-chloro-10- (2,4-difluorophenyl)-3- ((2- methoxyethoxy)meth- yl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.75-7.54 (m, 1H), 7.27-7.18 (m, 1H),7.08-6.95 (m, 2H), 6.67- 6.50 (m, 1H), 6.37 (t, J = 16.0 Hz, 1H),5.80-5.75 (m, 1H), 5.50-5.47 (m, 1H), 5.03-5.00 (m, 0.5H), 4.83- 4.69(m, 1H), 4.41-4.32 (m, 1.5H), 4.10-4.03 (m, 0.5H), 3.82-3.62 (m, 6.5H),3.54- 3.50 (m, 2H), 3.38-3.35 (m, 4H), 3.05-3.02 (m, 1H), 1.45-1.36 (m,6H). 605.2 502 (3S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-10- (5-chloro-2,4- difluorophenyl)-3- ((2-methoxyethoxy)meth- yl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

¹H NMR (400 MHz, CDCl₃) δ 7.56-7.53 (m, 1H), 7.32-7.28 (m, 1H),7.12-7.06 (m, 1H), 6.67- 6.50(m, 1H), 6.37 (t, J = 14.4 Hz, 1H),5.80-5.75 (m, 1H), 5.49-5.47 (m, 1H), 5.03-5.00 (m, 0.5H), 4.82- 4.68(m, 1H), 4.42-4.31 (m, 1.5H), 4.08-4.02 (m, 0.5H), 3.83-3.62 (m, 6.5H),3.55- 3.50 (m, 2H), 3.37-3.30 (m, 4H), 3.06-3.02 (m, 1H), 1.43-1.35 (m,6H). 639.2 506 (3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-9-chloro-3- (methoxymethyl)- 10-(2,4,5- trif1uorophenyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, MeOH-d₄) δ 7.90 (s, 1H), 7.46-7.27 (m, 2H), 6.83 (dd, J= 16.7, 10.6 Hz, 1H), 6.28 (dd, J = 16.7, 2.0 Hz, 1H), 5.80 (dd, J =10.6, 2.0 Hz, 1H), 5.40-5.31 (m, 1H), 1.57-1.50 (m, 3H), 1.43-1.36 (m,3H) 579.2 508 (3S,10S)-7- ((2S,5R)-4-acryloyl- 2,5- dimethylpiperazin-1-yl)-10-(2,4- difluorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, J = 12 Hz, 1H), 7.16 (q, J = 7.6 Hz,1H), 7.05-6.94 (m, 2H), 6.66-6.50 (m, 1H), 6.37 (t, J = 14.8 Hz, 1H),5.78 (t, J = 8.4 Hz, 1H), 5.45-5.43 (m, 1H), 5.08- 5.04 (m, 0.6H),4.82-4.65 (m, 1H), 4.43-4.33 (m, 1.4H), 4.11-4.17 (m, 0.5H), 3.73-3.61(m, 4H), 3.42- 3.31 (m, 4H), 3.26-3.21 (m, 0.5H), 3.01 (d, J = 13.6 Hz,1H), 1.50-1.41 (m, 6H). 595.2 509 (3S,10R)-7- ((2S,5R)-4-acryloyl- 2,5-dimethylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, J = 6.4 Hz, 1H), 7.19 (q, J = 8.0 Hz,1H), 7.04-6.94 (m, 2H), 6.66-6.50 (m, 1H), 6.37 (t, J = 14.8 Hz, 1H),5.77 (t, J = 9.2 Hz , 1H), 5.41-5.39 (m, 1H), 5.07-5.04 (m, 0.6H),4.80-4.66 (m, 1H), 4.44-4.35 (m, 1.4H), 4.15- 4.12 (m, 0.5H), 3.72-3.64(m, 4H), 3.39-3.32 (m, 4H), 3.26-3.22 (m, 0.5H), 3.02 (d, J = 13.2 Hz,1H), 1.49- 1.43 (m, 6H). 595.2 510 (3S,10S)-7- ((2S,5R)-4-acryloyl- 2,5-dimethylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-3- ((2-methoxyethoxy)meth- yl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.86-7.83 (m, 1H), 7.16 (q, J = 7.6 Hz, 1H),7.05-7.01 (m, 1H), 6.98-6.93 (m, 1H), 6.67- 6.51 (m, 1H), 6.37 (t, J =14.8 Hz, 1H), 5.78(t, J = 8.4 Hz, 1H), 5.48-5.41 (m, 1H), 5.11-5.03 (m,0.5H), 4.79-4.67 (m, 1H), 4.41- 4..35 (m, 1.5H), 4.11-4.08 (m, 0.5H),3.79-3.63 (m, 6H), 3.52 (t, J = 4.8 Hz, 2H), 3.42-3.38 (m, 1H), 3.35 (s,3H), 3.25-3.22 (m, 0.5H), 3.03-2.99 (m, 1H), 1.50-1.42 (m, 6H). 639.3511 (3S,10R)-7- ((2S,5R)-4-acryloyl- 2,5- dimethylpiperazin-1-yl)-10-(2,4- difluorophenyl)-3- ((2- methoxyethoxy)meth- yl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.86-7.83 (m, 1H), 7.18 (q, J = 8.0 Hz, 1H),7.04-6.94 (m, 2H), 6.67-6.50 (m, 1H), 6.37 (t, J = 15.6 Hz, 1H),5.80-5.75 (m, 1H), 5.46-5.36 (m, 1H), 5.11-5.01 (m, 0.5H), 4.78- 4.67(m, 1H), 4.45-4.31 (m, 1.5H), 4.16-4.12 (m, 0.5H), 3.78-3.60 (m, 6H),3.52 (t, J = 4.8 Hz, 2H), 3.41-3.38 (m, 1H), 3.35 (s, 3H), 3.26- 3.22(m, 0.5H), 3.03 (d, J = 13.2 Hz, 1H), 1.49-1.43 (m, 6H). 639.2 512(S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin- 1-yl)-10-(4-fluorophenyl)-3-((2- methoxyethoxy)meth- yl)-9- (trifluoromethyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, J = 10.0 Hz, 1H), 7.26-7.12 (m, 4H),6.70-6.48 (m, 1H), 6.37 (t, J = 15.0 Hz, 1H), 5.78 (t, J = 8.8 Hz, 1H),5.46-5.36 (m, 1H), 5.12-5.04 (m, 0.5H), 4.78-4.67 (m, 1H), 4.42 (d, J =13.6 Hz, 1H), 4.38-4.30 (m, 0.5H), 4.11 (m, 0.5H), 3.82-3.58 (m, 6H),3.52 (t, J = 4,6 Hz, 2H), 3.40-3.32 (m, 4H), 3.28-3.20 (m, 0.5H), 3.02-2.92 (m, 1H), 1.52-1.40 (m, 6H). 621.3 513 (3S)-7-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-3-(methoxymethyl)-9- (trifluoromethyl)- 2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.17 (q, J = 8.0 Hz, 1H), 7.06-6.93 (m, 2H), 6.62 (dd, J = 10.4 Hz, 16.8 Hz, 1H), 6.40 (dd, J = 2.0 Hz,16.8 Hz, 1H), 5.77 (dd, J = 2.0 Hz, 10.4 Hz, 1H), 5.48-5.41 (m, 1H),4.79-4.53 (m, 2H), 4.21-4.16 (m, 2H), 3.69- 3.59 (m, 2H), 3.37-3.30 (m,6H), 3.05-2.99 (m, 1H), 1.62 (d, J = 6.8 Hz, 3H), 1.47 (d, J = 6.8 Hz,3H). 595.2 514 (3S)-7-(4- acryloylpiperazin-1- yl)-10-(2,4-difluorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 1H), 7.18 (q, J = 6.4 Hz, 1H), 7.05-6.93 (m, 2H), 6.59 (dd, J = 10.4 Hz, 16.8 Hz, 1H), 6.37 (dd, J = 2.0 Hz,16.8 Hz, 1H), 5.78 (dd, J = 2.0 Hz, 10.4 Hz, 1H), 5.47-5.39 (m, 1H),4.00-3.92 (m, 3H), 3.81-3.78 (m, 5H), 3.69- 3.60 (m, 2H), 3.39 (s, 3H),3.37-3.33 (m, 1H), 3.04- 2.98 (m, 1H). 567.2 515 (S)-7-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-9-chloro-3-((4- (2,2-difluoroethyl)pipera- zin-1-yl)methyl)-10- (4-fluorophenyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.52 (s, 1H), 7.26-7.16 (m, 4H), 6.66- 6.51(m, 1H), 6.40-6.33 (m, 1H), 5.99-5.70 (m, 2H), 5.41-5.36 (m, 1H), 4.98-4.72 (m, 1.5H), 4.39-4.22 (m, 1H), 4.00-3.97 (m, 0.5H), 3.83-3.65 (m,2H), 3.36-3.27 (m, 1.5H), 3.00- 2.96 (m, 1H), 2.80-2.61 (m, 5.5H),2.61-2.50 (m, 7H), 1.39-1.30 (m, 6H). 661.3 516 (S)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-10-(4- fluorophenyl)-3-((methoxymethoxy) methyl)-9- (trifluoromethyl)- 2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.21-7.14 (m, 4H), 6.66- 6.51(m, 1H), 6.39 (d, J = 16.8 Hz, 1H), 5.79 (d, J = 8 Hz, 1H), 5.41 (s,1H), 4.68- 4.62 (m, 3H), 4.53-4.30 (m, 2H), 3.99-3.94 (m, 1H), 3.83-3.79(m, 2H), 3.65- 3.43 (m, 2.5H), 3.37 (s, 3H), 3.35-3.33 (m, 0.5H),3.09-2.98 (m, 2H), 1.55- 1.49 (m, 3H). 593.3 517 (S)-7-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-9-chloro-3-((4-cyclopropylpiperazin- 1-yl)methyl)-10- (4-fluorophenyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.52 (s, 1H), 7.24-7.19 (m, 4H), 6.67- 6.49(m, 1H), 6.36 (t, J = 14.4 Hz, 1H), 5.79-5.73 (m, 1H), 5.47-5.37 (m,1H), 5.02-4.69 (m, 2H), 4.42- 3.97 (m, 2H), 3.86-3.61 (m, 2H), 3.40-3.29(m, 1H), 3.05-2.94 (m, 1H), 2.83- 2.48 (m, 10H) , 1.39-1.24 (m, 7H),0.57-0.36 (m, 4H). 637.3 518 (3S)-7-((S)-4- acryloyl-2-methylpiperazin-1- yl)-10-(5-chloro- 2,4-difluorophenyl)- 3-((methoxymethoxy) methyl)-9- (trifluoromethyl)- 2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.78 (s, 1H), 7.31-7.24 (m, 1H), 7.10- 7.04(m, 1H), 6.67-6.50 (m, 1H), 6.38 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.79 (d,J = 10.4 Hz, 1H), 5.50-5.38 (m, 1H), 4.80-4.62 (m, 3H), 4.59-4.26 (m,2H), 4.06- 3.92 (m, 0.5H), 3.90-3.74 (m, 2.5H), 3.67-3.47 (m, 1.5H),3.46-3.33 (m, 4.5H), 3.17-2.96 (m, 2H), 1.61- 1.44 (m, 3H). 645.2 519(3S)-3-((1S,4S)-2- oxa-5- azabicyclo[2.2.1]hep- tan-5-ylmethyl)-7-((2S,5R)-4-acryloyl- 2,5- dimethylpiperazin- 1-yl)-9-chloro-10- (2,4-difluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.55-7.52 (m, 1H), 7.25-7.18 (m, 1H),7.07-6.96 (m, 2H), 6.66- 6.50 (m, 1H), 6.41-6.33 (m, 1H), 5.79-5.75 (m,1H), 5.28-5.26 (m, 1H), 5.01- 4.70 (m, 2H), 4.40-4.32 (m, 2H), 4.04-3.30(m, 9H), 3.03-2.84 (m, 5H), 1.42- 1.33 (m, 6H). 628.2 520 (3S)-7-((S)-4-acryloyl-2- methylpiperazin-1- yl)-9-chloro-3-((4- cyclopropylpiperazin-1-yl)methyl)-10- (2,4,5- trifluorophenyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.49 (s, 1H), 7.14-7.04 (m, 2H), 6.66- 6.50(m, 1H), 6.37 (dd, J = 2.0 Hz, J = 1.2 Hz, 1H) , 5.78 (d, J = 11.6 Hz,1H), 5.41-5.31 (m, 1H), 4.76- 3.79 (m, 5H), 3.56-3.39 (m, 4H), 3.09-3.04(m, 3H), 2.95-2.52 (m, 8H), 1.50- 1.43 (m, 4H), 0.87-0.35 (m, 3H). 659.3521 (3S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-10-(5-chloro- 2,4-difluorophenyl)- 3-((4-(2,2-difluoroethyl)pipera- zin-1-yl)methyl)-9- (trifluoromethyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.83 (s, 1H), 7.09-7.04 (m, 1H), 6.66- 6.50(m, 1H), 6.37 (t, J = 14.0 Hz, 1H), 6.00-5.72 (m, 2H), 5.42-5.31 (m,1H), 5.08-4.64 (m, 2H), 4.43- 4.33 (m, 1H), 4.12-4.01 (m, 1H), 3.72-3.64(m, 3H), 3.41-3.01 (m, 4H), 2.79- 2.53 (m, 10H), 1.47-1.37 (m, 6H).747.3 522 (3S)-7-((S)-4- acryloyl-2- methylpiperazin-1- yl)-3-((methoxymethoxy) methyl)-9- (trifluoromethyl)- 10-(2,4,5-trifluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.78 (s, 1H), 7.13-7.00 (m, 2H), 6.70- 6.48(m, 1H), 6.38 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.79 (d, J = 10.4 Hz, 1H),5.52- 5.37 (m, 1H), 4.78-4.60 (m, 3H), 4.58-4.26 (m, 2H), 4.06-3.92 (m,0.5H), 3.89- 3.74 (m, 2.5H), 3.69-3.42 (m, 1.5H), 3.42-3.27 (m, 4.5H),3.98-3.16 (m, 2H), 1.62-1.42 (m, 3H). 629.2 523 (3S)-7-(9-acryloyl-7,7-difluoro-3,9- diazabicyclo[3.3.1] nonan-3-yl)-10-(2,4-difluorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 8.01-7.94 (m, 1H), 7.21-7.15 (m, 1H),7.05-6.94 (m, 2H), 6.63- 6.56 (m, 1H), 6.43 (dd, J = 1.6 Hz, 16.8 Hz,1H), 5.86 (d, J = 10 Hz, 1H), 5.44- 5.33 (m, 1H), 5.16-5.15 (m, 1H),4.77-4.69 (m, 1H), 4.55-4.51 (m, 1H), 4.38- 4.28 (m, 1H), 3.66-3.50 (m,3H), 3.39-3.32 (m, 4H), 3.04-2.98 (m, 1H), 2.60- 2.32 (m, 4H), 2.04-1.98(m, 1H). 643.2 544 (3S,10S)-7- ((2S,5R)-4-acryloyl- 2,5-dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4-difluorophenyl)-3-(methoxymethyl)- 9-(trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, J = 10.8 Hz, 1H), 7.26-7.23 (m, 1H),7.07 (t, J = 8.8 Hz, 1H), 6.67-6.50 (m, 1H), 6.37 (t, J = 14.0 Hz, 1H),5.78 (t, J = 8.8 Hz , 1H), 5.46-5.41 (m, 1H), 5.09-5.03 (m, 0.6H),4.80-4.65 (m, 1H), 4.44-4.33 (m, 1.4H), 4.10- 4.07 (m, 0.5H), 3.72-3.63(m, 4H), 3.39-3.34 (m, 4H), 3.25-3.21 (m, 0.5H), 3.05- 3.01 (m, 1H),1.50-1.44 (m, 6H). 629.2 545 (3S,10R)-7- ((2S,5R)-4-acryloyl- 2,5-dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4-difluorophenyl)-3-(methoxymethyl)- 9-(trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.84-7.84 (m, 1H), 7.30-7.28 (m, 1H), 7.07 (t,J = 8.4 Hz, 1H), 6.66-6.50 (m, 1H), 6.37 (t, J = 14.0 Hz, 1H), 5.80-5.75(m, 1H), 5.44-5.40 (m, 1H), 5.08-5.03 (m, 0.6H), 4.80- 4.66 (m, 1H),4.44-4.34 (m, 1.4H), 4.13-4.09 (m, 0.5H), 3.75-3.65 (m, 4H), 3.41- 3.35(m, 4H), 3.26-3.23 (m, 0.5H), 3.05-3.02 (m, 1H), 1.49-1.42 (m, 6H).629.2 546 (3S,10S)-7- ((3S,5R)-4-acryloyl- 3,5- dimethylpiperazin-1-yl)-10-(2,4- difluorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.18 (q, J = 8.0 Hz, 1H), 7.05-6.93 (m, 2H), 6.62 (dd, J = 6.0 Hz, 16.4 Hz, 1H), 6.40 (dd, J = 1.6 Hz,16.4 Hz, 1H), 5.77 (dd, J = 1.6 Hz, 10.4 Hz, 1H), 5.48-5.45 (m, 1H),4.70-4.60 (m, 1H), 4.22-4.17 (m, 2H), 3.74- 3.60 (m, 3H), 3.39-3.31 (m,6H), 3.03-2.99 (m, 1H), 1.63-1.61 (m, 3H), 1.47 (d, J = 7.2 Hz, 3H).595.2 547 (3S,10R)-7- ((3S,5R)-4-acryloyl- 3,5- dimethylpiperazin-1-yl)-10-(2,4- difluorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.18 (q, J = 7.6 Hz, 1H), 7.04-6.94 (m, 2H), 6.62 (dd, J = 10.0 Hz, 16.8 Hz, 1H), 6.40 (dd, J = 2.0 Hz,16.8 Hz, 1H), 5.77 (dd, J = 2.0 Hz, 10.8 Hz, 1H), 5.46-5.42 (m, 1H),4.73-4.61 (m, 1H), 4.21-4.16 (m, 2H), 3.74- 3.64 (m, 3H), 3.40-3.30 (m,6H), 3.03 (dd, J = 2.4 Hz, 13.2 Hz, 1H), 1.63-1.61 (m, 3H), 1.47 (d, J =7.2 Hz, 3H). 595.2 548 (3S,10R)-7-((S)-4- acryloyl-2- methylpiperazin-1-yl)-10-(2,4- difluorophenyl)-3- ((methoxymethoxy) methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.18 (q, J = 8.0 Hz, 1H), 7.04-6.95 (m, 2H), 6.66-6.51 (m, 1H), 6.40 (d, J = 16.8 Hz, 1H), 5.79 (d, J =10.4 Hz, 1H), 5.427-5.425 (m, 1H), 4.71-4.62 (m, 3H), 4.54- 4.34 (m,2H), 4.02-3.96 (m, 1H), 3.81-3.79 (m, 2H), 3.63-3.60 (m, 1H), 3.52- 3.39(m, 2H), 3.35 (s, 3H), 3.09-3.01 (m, 2H), 1.58- 1.51 (m, 3H). 611.3 549(3S,10S)-7-((S)-4- acryloyl-2- methylpiperazin-1- yl)-10-(2,4-difluorophenyl)-3- ((methoxymethoxy) methyl)-9- (trifluoromethyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.78 (s, 1H), 7.20-7.15 (m, 1H), 7.03 (t, J =7.6 Hz, 1H), 6.98-6.93 (m, 1H), 6.64-6.51 (m, 1H), 6.39 (d, J = 16.4 Hz,1H), 5.79 (d, J = 9.6 Hz, 1H), 5.46-5.45 (m, 1H), 4.72- 4.62 (m, 3H),4.51-4.28 (m, 2H), 3.97-3.94 (m, 1H), 3.82-3.78 (m, 2H), 3.64- 3.53 (m,1H), 3.49-3.38 (m, 2H), 3.38 (s, 3H), 3.07-3.05 (m, 2H), 1.56-1.50 (m,3H). 611.2 550 (3S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-3-((4- (2,2- difluoroethyl)pipera- zin-1-yl)methyl)-10-(2,4- difluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.54 (s, 1H), 7.21 (q, J = 8.4 Hz, 1H), 7.07-6.95 (m, 2H), 6.66-6.50 (m, 1H), 6.37 (t, J = 14.8 Hz, 1H), 5.99-5.71(m, 2H), 5.48-5.38 (m, 1H), 5.01- 4.70 (m, 1.5H), 4.39-4.24 (m, 1.5H),4.07-3.97 (m, 0.5H), 3.80-3.65 (m, 2.5H), 3.40-3.26 (m, 1.5H), 3.09-2.99 (m, 1.5H), 2.84-2.64 (m, 5.5H), 2.64-2.45 (m, 5.5H), 1.45-1.25 (m,6H). 679.2 551 (3S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-3-((4- cyclopropylpiperazin- 1-yl)methyl)-10- (2,4-difluorophenyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.53 (s, 1H), 7.22 (q, J = 8.0 Hz, 1H), 7.07-6.95 (m, 2H), 6.66-6.50 (m, 1H), 6.37 (t, J = 16.8 Hz, 1H), 5.79-5.75(m, 1H), 5.49-5.38 (m, 1H), 4.99- 4.72 (m, 1.5H), 4.40-4.22 (m, 1.5H),4.01-3.99 (m, 0.5H), 3.82-3.65 (m, 2.5H), 3.37-3.28 (m, 1H), 3.06- 3.03(m, 1H), 2.95-2.45 (m, 10H), 1.47-1.30 (m, 7H), 0.84-0.15 (m, 4H). 655.3552 (3S,10R)-7-((S)-4- acryloyl-2- methylpiperazin-1- yl)-10-(5-chloro-2,4-difluorophenyl)- 3- ((methoxymethoxy) methyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.78 (m, 1H), 7.31-7.24 (m, 1H), 7.08 (t, J =8.8 Hz, 1H), 6.67-6.50 (m, 1H), 6.38 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.79(d, J = 10.0 Hz, 1H), 5.50-5.38 (m, 1H), 4.80-4.62 (m, 3H), 4.59-4.29(m, 2H), 4.06- 3.92 (m, 0.5H), 3.89-3.75 (m, 2.5H), 3.67-3.47 (m, 1.5H),3.46-3.32 (m, 4.5H), 3.15-2.97 (m, 2H), 1.58- 1.46 (m, 3H). 645.2 553(3S,10S)-7-((S)-4- acryloyl-2- methylpiperazin-1- yl)-10-(5-chloro-2,4-difluorophenyl)- 3- ((methoxymethoxy) methyl)-9- (trifluoromethyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.78 (m, 1H), 7.30-7.24 (m, 1H), 7.07 (td, J =8.8 Hz, 2 Hz, 1H), 6.67- 6.50 (m, 1H), 6.38 (d, J = 16.8 Hz, 1H), 5.79(d, J = 10.4 Hz, 1H), 5.51-5.40 (m, 1H), 4.78-4.60 (m, 3H), 4.59-4.26(m, 2H), 4.04- 3.92 (m, 0.5H), 3.88-3.74 (m, 2.5H), 3.67-3.47 (m, 1.5H),3.46-3.32 (m, 4.5H), 3.15-2.97 (m, 2H), 1.58- 1.45 (m, 3H). 645.2 554(3S,10S)-7- ((2S,5R)-4-acryloyl- 2,5- dimethylpiperazin-1-yl)-10-(5-chloro- 2,4-difluorophenyl)- 3-((2- methoxyethoxy)meth-yl)-9- (trifluoromethyl)- 2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

¹H NMR (400 MHz, CDCl₃) δ 7.86-7.83 (m, 1H), 7.23-7.21 (m, 1H), 7.06 (t,J = 4.8 Hz, 1H), 6.67-6.51 (m, 1H), 6.38 (t, J = 14.4 Hz, 1H), 5.78 (t,J = 8.8 Hz, 1H), 5.48-5.40 (m, 1H), 5.10-5.02 (m, 0.5H), 4.77-4.65 (m,1H), 4.44-4.34 (m, 1.5H), 4.11- 4.07 (m, 0.5H), 3.76-3.70 (m, 4H),3.68-3.61 (m, 2H), 3.52 (t, J = 4.8 Hz, 2H), 3.42 (d, J = 12.8 Hz, 1H),3.36 (s, 3H), 3.24-3.21 (m, 0.5H), 3.04-3.00 (m, 1H), 1.50-1.42 (m, 6H).673.2 555 (3S,10R)-7- ((2S,5R)-4-acryloyl- 2,5- dimethylpiperazin-1-yl)-10-(5-chloro- 2,4-difluorophenyl)- 3-((2- methoxyethoxy)meth-yl)-9- (trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.844 (d, J = 8.4 Hz, 1H), 7.293-7.27 (m, 1H),7.07 (t, J = 4.8 Hz, 1H), 6.67-6.50 (m, 1H), 6.37 (m, 1H), 5.78 (t, J =8.8 Hz, 1H), 5.48-5.40 (m, 1H), 5.11-5.00 (m, 0.5H), 4.81-4.77 (m, 1H),4.44- 4.31 (m, 1.5H), 4.13- 4.09 (m, 0.5H), 3.78-3.61 (m, 4H), 3.68-3.61(m, 2H), 3.53 (t, J = 4.8 Hz, 2H), 3.43 (d, J = 13.6 Hz, 1H), 3.36 (s,3H), 3.26-3.21 (m, 0.5H), 3.05-3.01 (m, 1H), 1.50-1.42 (m, 6H). 673.2556 (3S,10R)-7- ((2S,5R)-4-acryloyl- 2,5- dimethylpiperazin-1-yl)-10-(5-chloro- 2,4-difluorophenyl)- 3-((4-(2,2-difluoroethyl)pipera- zin-1-yl)methyl)-9- (trifluoromethyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.87(s, 1H), 7.10 (t, J = 11.6 Hz, 1H), 6.71-6.53 (m, 1H), 6.46-6.37 (m, 1H), 6.10-5.69 (m, 1H), 5.85-5.79 (m, 1H),5.49- 5.39 (m, 1H), 5.14-4.69 (m, 2H), 4.48-4.37 (m, 1H), 4.17-4.08 (m,1H), 3.80- 3.65 (m, 3H), 3.46-3.26 (m, 2H), 3.11-3.00 (m, 2H), 2.80-2.56(m, 10H), 1.51- 1.40 (m, 6H). 747.3 557 (3S,10S)-7- ((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4-difluorophenyl)-3-((4-(2,2- difluoroethyl)pipera- zin-1-yl)methyl)-9- (trifluoromethyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.90 (s, 1H), 7.14 (t, J = 12.0 Hz, 1H), 6.68-6.49 (m, 1H), 6.42-6.33 (m, 1H), 6.07-5.65 (m, 1H), 5.81-5.76 (m, 1H),5.42- 5.32 (m, 1H), 5.09-4.64 (m, 2H), 4.45-4.40 (m, 1H), 4.11-4.01 (m,1H), 3.78- 3.63(m, 3H), 3.43-3.24(m, 2H), 3.11-2.99(m, 2H), 2.78-2.54(m, 10H), 1.51- 1.45 (m, 6H). 747.3 558 (S)-7-((2S,5R)-4- acryloyl-2,5-dimethylpiperazin- 1-yl)-9-chloro-10- (4-fluorophenyl)-3- ((2-methoxyethoxy)meth- yl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one

¹H NMR (400 MHz, CDCl₃) δ 7.56-7.53 (m, 1H), 7.24-7.17 (m, 4H),6.67-6.50 (m, 1H), 6.41- 6.33 (m, 1H), 5.80-5.75 (m, 1H), 5.50-5.45 (m,1H), 5.04-4.98 (m, 0.5H), 4.86- 4.68 (m, 1H), 4.41-4.33 (m, 1.5H),4.08-4.03 (m, 0.5H), 3.83-3.64 (m, 6.5H), 3.54- 3.51 (m, 2H), 3.36-3.19(m, 4H), 3.01-2.97 (m, 1H), 1.44-1.36 (m, 6H). 587.2 559(3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(5-chloro-2,4-difluorophenyl)- 3-(methoxymethyl)- 9-(trifluoromethyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.28-7.24 (m, 1H), 7.09- 7.04(m, 1H), 6.65-6.59 (m, 1H), 6.40 (dd, J = 1.6 Hz, 16.8 Hz, 1H), 5.77(dd, J = 1.6 Hz, 10.8 Hz, 1H), 5.50- 5.43 (m, 1H), 4.75-4.59 (m, 2H),4.21-4.15 (m, 2H), 3.67-3.62 (m, 2H), 3.41- 3.30 (m, 6H), 3.05-3.01 (m,1H), 1.62-1.61 (m, 3H), 1.49 (d, J = 7.2 Hz, 3H). 629.1 560(3S)-3-((1S,4S)-2- oxa-5- azabicyclo[2.2.1]hep- tan-5-ylmethyl)-7-((3S,5R)-4-acryloyl- 3,5- dimethylpiperazin- 1-yl)-10-(2,4-difluorophenyl)-9- (trifluoromethyl)- 2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.21-7.14 (m, 1H), 7.06- 6.93(m, 2H), 6.66-6.59 (m, 1H), 6.43-6.38 (m, 1H), 5.77 (d, J = 12.0 Hz,1H), 5.28-5.24 (m, 1H), 4.74- 4.60 (m, 2H), 4.43-4.37 (m, 1H), 4.19 (d,J = 13.6 Hz, 2H), 3.91-3.84 (m, 1H), 3.69-3.31 (m, 5.5H), 2.99- 2.85 (m,4.5H), 1.75-1.66 (m, 2H), 1.60-1.58 (m, 3H), 1.49-1.41 (m, 3H). 662.3561 2-(4-(((3S)-7- ((2S,5R)-4-acryloyl- 2,5- dimethylpiperazin-1-yl)-10-(2,4- difluorophenyl)-5- oxo-9- (trifluoromethyl)-3,5-dihydro-2H- [1,4]thiazino[2,3,4- ij]quinazolin-3-yl)methyl)piperazin- 1-yl)acetonitrile

¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J = 2.0 Hz, 1H), 7.24-7.18 (m, 1H),7.06-6.96 (m, 2H), 5.50- 5.43 (m, 1H), 4.63-4.54 (m, 1H), 4.18-4.12 (m,1H), 3.59-3.47 (m, 1H), 3.14- 2.84 (m, 8H), 2.40-2.34 (m, 2H), 1.95-1.69(m, 7H), 1.52(dd, J = 1.6 Hz, 1.6 Hz, 3H), 1.44-1.31 (m, 3H), 1.08-1.04(m, 3H). 688.3 562 (3S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-3-((4-(2,2- difluoroethyl)pipera- zin-1-yl)methyl)-10- (2,4-difluorophenyl)-9- (trifluoromethyl)- 2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.87 (s, 1H), 7.26-7.17 (m, 1H), 7.10- 6.98(m, 2H), 6.76-6.54 (m, 1H), 6.46-6.38 (m, 1H), 6.11-5.70 (m, 1H), 5.85-5.79 (m, 1H), 5.47-5.35 (m, 1H), 5.13-5.07 (m, 0.5H), 4.85-4.70 (m, 1H),4.48- 4.37 (m, 1.5H), 4.19-4.05 (m, 1H), 3.79-3.64 (m, 2H), 3.44-5.28(m, 2H), 3.11- 3.02 (m, 1H), 2.79-2.53 (m, 11H), 1.51-1.42 (m, 6H).713.3 563 (3S,10R)-7- ((3S,5R)-4-acryloyl- 3,5- dimethylpiperazin-1-yl)-10-(5-chloro- 2,4-difluorophenyl)- 3-(methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.28-7.24 (m, 1H), 7.07 (t, J =8.8 Hz, 1H), 6.65-6.59 (m, 1H), 6.40 (dd, J = 1.6 Hz, 16.8 Hz, 1H), 5.77(dd, J = 1.2 Hz, 10.0 Hz, 1H), 5.45-5.44 (m, 1H), 4.73- 4.58 (m, 2H),4.21-4.15 (m, 2H), 3.67-3.64 (m, 2H), 3.41-3.31 (m, 6H), 3.05- 3.01 (m,1H), 1.61 (m, J = 6.8 Hz, 3H), 1.47 (d J = 6.8 Hz, 3H). 629.2 564(3S,10S)-7- ((3S,5R)-4-acryloyl- 3,5- dimethylpiperazin-1-yl)-10-(5-chloro- 2,4-difluorophenyl)- 3-(methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.28-7.25 (m, 1H), 7.07 (t, J =8.8 Hz, 1H), 6.65-6.59 (m, 1H), 6.40 (dd, J = 1.6 Hz, 16.4 Hz, 1H), 5.77(dd, J = 1.6 Hz, 10.4 Hz, 1H), 5.48-5.45 (m, 1H), 4.76- 4.59 (m, 2H),4.21-4.16 (m, 2H), 3.68-3.59 (m, 2H), 3.39-3.30 (m, 6H), 3.04- 3.00 (m,1H), 1.61-1.59 (m, 3H), 1.46 (d, J = 6.4 Hz, 3H). 629.2 565(3S,10S)-3-((2-oxa- 7- azaspiro[3.5]nonan- 7-yl)methyl)-7-((3S,5R)-4-acryloyl- 3,5- dimethylpiperazin- 1-yl)-10-(5-chloro-2,4-difluorophenyl)- 9-(trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.28-7.27 (m, 1H), 7.07 (t, J =8.4 Hz, 1H), 6.65-6.58 (m, 1H), 6.43-6.38 (dd, J = 1.6 Hz, 16.8 Hz, 1H),5.79- 5.76 (dd, J = 1.6 Hz, 10.4 Hz, 1H), 5.34-5.29 (m, 1H), 4.67-4.65(m, 2H), 4.39- 4.37 (m, 4H), 4.20-4.15 (m, 2H), 3.47-3.06 (m, 3H),3.01-2.97 (m, 1H), 2.74- 2.58 (m, 3H), 2.54-2.29 (m, 3H), 1.83-1.81 (m,4H), 1.61-1.59 (m, 3H), 1.48- 1.46 (m, 3H). 724.2 566(3S,10R)-3-((2-oxa- 7- azaspiro[3.5]nonan- 7-yl)methyl)-7-((3S,5R)-4-acryloyl- 3,5- dimethylpiperazin- 1-yl)-10-(5-chloro-2,4-difluorophenyl)- 9-(trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.28-7.27 (m, 1H), 7.07 (t, J =8.8 Hz, 1H), 6.65-6.58 (m, 1H), 6.43-6.38 (dd, J = 1.6 Hz, 16.4 Hz, 1H),5.78- 5.76 (dd, J = 1.6 Hz, 10.4 Hz, 1H), 5.33-5.32 (m, 1H), 4.67-4.60(m, 2H), 4.39- 4.37 (m, 4H), 4.19-4.16 (m, 2H), 3.46-3.30 (m, 3H),3.01-2.98 (m, 1H), 2.77- 2.60 (m, 3H), 2.46-2.35 (m, 3H), 1.84-1.82 (m,4H), 1.61-1.59 (m, 3H), 1.49- 1.48 (m, 3H). 724.2 567 (3S)-7-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(5-chloro-2,4-difluorophenyl)- 3- ((methoxymethoxy) methyl)-9- (trifluoromethyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.29-7.27 (m, 1H), 7.10- 7.04(m, 1H), 6.65-6.59 (m, 1H), 6.42 (dd, J = 1.6 Hz, 16.4 Hz, 1H), 5.78(dd, J = 1.6 Hz, 10.4 Hz, 1H), 5.50- 5.46 (m, 1H), 4.68-4.62 (m, 4H),4.214.17 (m, 2H), 3.80-3.76 (m, 2H), 3.42- 3.32 (m, 6H), 3.09-3.04 (m,1H), 1.59 (d, J = 2.8 Hz, 3H), 1.49-1.46 (m, 3H). 659.3 568(3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(5-chloro-2,4-difluorophenyl)- 3-(hydroxymethyl)- 9-(trifluoromethyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.26-7.23 (m, 1H), 7.10- 7.04(m, 1H), 6.65-6.58 (m, 1H), 6.43 (dd, J = 1.2 Hz, 16.8 Hz, 1H),5.79-5.76 (m, 1H), 5.37-5.34 (m, 1H), 4.73-4.61 (m, 2H), 4.23- 4.20 (m,2H), 4.00-3.87 (m, 2H), 3.45-3.31 (m, 3H), 3.09-3.05 (m, 1H), 1.80- 1.73(m, 1H), 1.63 (d, J = 7.2 Hz, 3H), 1.46-1.43 (m, 3H). 615.3 569(3S,10R)-7- ((2S,5R)-4-acryloyl- 2,5- dimethylpiperazin-1-yl)-9-chloro-3-((4- (2,2- difluoroethyl)pipera- zin-1-yl)methyl)-10-(1-methyl-1H- indazol-7-yl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.62(d, J = 12.8 Hz, 1H), 7.30-7.28 (m, 1H),7.15 (d, J = 6.8 Hz, 1H),6.75-6.51 (m, 1H), 6.38 (t, J = 14.0 Hz, 1H), 5.99-5.69 (m, 2H), 5.37-5.33 (m, 1H), 5.07 (m, 0.5H), 4.82-4.70 (m, 1H), 4.45-4.35 (m, 1.5H),4.15 (m, 0.5H), 3.78-3.61 (m, 5.5H), 3.33-3.24 (m, 2H), 3.07-3.05 (m,1H), 2.73- 2.51 (m, 11H), 1.50-1.43 (m, 6H). 697.3 570 (3S,10S)-7-((2S,5R)-4-acryloyl- 2,5- dimethylpiperazin- 1-yl)-9-chloro-3-((4- (2,2-difluoroethyl)pipera- zin-1-yl)methyl)-10- (1-methyl-1H-indazol-7-yl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.59(m, 1H), 7.24-7.22 (m, 1H), 7.12 (d, J = 6.8 Hz, 1H), 6.67-6.51 (m, 1H),6.38 (t, J = 15.6 Hz, 1H), 5.99-5.71 (m, 2H), 5.51-5.45 (m, 1H),5.01-4.77 (m, 1.5H), 4.42- 4.35 (m, 1H), 3.84-3.62 (m, 6H), 3.42-3.23(m, 2.5H), 3.01 (m, 2H), 2.73-2.56 (m, 10H), 1.42-1.32 (m, 6H). 697.3571 (3S)-7-(9-acryloyl- 7-oxo-3,9- diazabicyclo[3.3.1]nonan-3-yl)-10-(2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)- 2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.85 (s, 1H), 7.19-7.13 (m, 1H), 7.05- 6.94(m, 2H), 6.72-6.64 (m, 1H), 6.49-6.45 (m, 1H), 5.90 (d, J = 10.4 Hz,1H), 5.50-5.36 (m, 2H), 4.78- 4.73 (m, 1H), 4.26-4.14 (m, 2H), 3.67-3.57(m, 2H), 3.36-3.22 (m, 6H), 3.04- 2.98 (m, 1H), 2.90-2.75 (m, 3H),2.67-2.57 (m, 1H). 621.2 572 (3S)-7-(4- acryloylpiperazin-1-yl)-10-(5-chloro- 2,4-difluorophenyl)- 3-(methoxymethyl)-9-(trifluoromethyl)- 2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.29-7.27 (m, 1H), 7.09- 7.05(m, 1H), 6.62-6.55 (m, 1H), 6.37 (dd, J = 1.6 Hz, 16.8 Hz, 1H), 5.90(dd, J = 1.2 Hz, 10.4 Hz, 1H), 5.46- 5.41 (m, 1H), 3.99-3.91 (m, 3H),3.80-3.79 (m, 5H), 3.67-3.63 (m, 2H), 3.41- 3.36 (m, 4H), 3.04-3.00 (m,1H). 601.1 573 (S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-9-chloro-10- (4-fluorophenyl)-3- (methoxymethyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.60 (s, 1H), 7.29-7.22 (m, 4H), 6.67- 6.58(m, 1H), 6.45-6.43 (m, 1H), 5.85-5.80 (m, 1H), 5.52-5.50 (m, 1H), 5.07-5.06 (m, 0.5H), 4.91-4.87 (m, 0.5H), 4.78-4.75 (m, 0.5H), 4.41-4.36 (m,1H), 4.15-4.07 (m, 1H), 3.84- 3.77 (m, 2H), 3.74-3.67 (m, 2H), 3.44 (s,3H), 3.35- 3.31(m, 1.5H) , 3.05-3.01 (m, 1H), 1.50-1.40 (m, 6H). 543.2574 (S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin- 1-yl)-3-((4-(2,2-difluoroethyl)pipera- zin-1-yl)methyl)-10- (4-fluorophenyl)-9-(trifluoromethyl)- 2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 7.90 (s, 1H), 7.28-7.21 (m, 4H), 6.70- 6.40(m, 2H), 6.12-5.82 (m, 2H), 5.42-5.38 (m, 1H), 5.13-5.10 (m, 0.5H),4.86- 4.73 (m, 1H), 4.50-4.38 (m, 1.5H), 3.77-3.73 (m, 2H), 3.41-3.30(m, 2H), 3.06- 2.97(m, 1H), 2.91-2.80 (m, 4H) , 2.72-2.64 (m, 4H),1.66-1.65 (m, 3H), 1.56- 1.49 (m, 4H), 1.25-1.23 (m, 3H). 659.3 5752-(4-(((3S)-7- ((2S,5R)-4-acryloyl- 2,5- dimethylpiperazin-1-yl)-10-(2,4- difluorophenyl)-5- oxo-9- (trifluoromethyl)-3,5-dihydro-2H- [1,4]thiazino[2,3,4- ij]quinazolin-3-yl)methyl)piperazin- 1-yl)acetamide

¹H NMR (400 MHz, CDCl₃) δ 7.84 (s, 1H), 7.21-7.14 (m, 1H), 7.05- 6.94(m, 2H), 6.66-6.50 (m, 1H), 6.37 (t, J = 14.8 Hz, 1H), 5.78 (t, J = 8.4Hz, 1H), 5.45-5.27 (m, 2H), 5.05-5.02 (m, 0.5H), 4.78- 4.67 (m, 1H),4.41-4.35 (m, 1.5H), 4.10-4.05 (m, 0.5H), 3.75-3.50 (m, 3H), 3.36- 2.95(m, 5.5H), 2.93-2.50 (m, 9H), 1.49-1.39 (m, 6H). 706.3 576(3S,10S)-3-(2-oxa- 7- azaspiro[3.5]nonan- 7-ylmethyl)-7-((3S,5R)-4-acryloyl- 3,5- dimethylpiperazin- 1-yl)-10-(2,4-difluorophenyl)-9- (trifluoromethyl)- 2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.18 (q, J = 8.4 Hz, 1H), 7.06-6.94 (m, 2H), 6.65-6.59 (m, 1H), 6.40 (dd, J = 16.8 Hz, 2.0 Hz, 1H),5.77 (dd, J = 10.4 Hz, 1.6 Hz, 1H), 5.37- 5.35 (m, 1H), 4.72-4.65 (m,2H), 4.46-4.32 (m, 4H), 4.20-4.17 (m, 2H), 3.48- 3.30 (m, 3H), 3.00-2.96(m, 1H), 2.76-2.66 (m, 1H), 2.65-2.51 (m, 2H), 2.47- 2.28 (m, 3H),1.82-1.81 (m, 4H), 1.61-1.60 (m, 3H), 1.48 (d, J = 6.4 Hz, 3H). 690.2577 (3S)-3-(2-oxa-7- azaspiro[3.5]nonan- 7-ylmethyl)-7-((3S,5R)-4-acryloyl- 3,5- dimethylpiperazin- 1-yl)-10-(2,4-difluorophenyl)-9- (trifluoromethyl)- 2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.17 (q, J = 8.0 Hz, 1H), 7.04-6.95 (m, 2H), 6.65-6.59 (m, 1H), 6.42-6.38 (m, 1H), 5.78-5.76 (dd, J =10.4 Hz, 1.6 Hz, 1H), 5.32-5.31 (m, 1H), 4.66-4.57 (m, 2H), 4.44-4.32(m, 4H), 4.20- 4.16 (m, 2H), 3.44-3.30 (m, 3H), 3.07-2.98 (m, 1H),2.76-2.71 (m, 1H), 2.68- 2.52 (m, 2H), 2.49-2.27 (m, 3H), 1.80-1.71 (m,4H), 1.62-1.60 (m, 3H), 1.49- 1.42 (m, 3H). 690.3 578 (3S,10R)-7-(4-acryloylpiperazin-1- yl)-10-(2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.80 (s, 1H),7.18 (q, J = 8.0 Hz, 1H), 7.04-6.95 (m, 2H), 6.59 (dd, J = 10.8 Hz, 16.8 Hz, 1H), 6.37 (d, J = 15.6 Hz,1H), 5.78 (dd, J = 1.2 Hz, 10.0 Hz, 1H), 5.44-5.39 (m, 1H), 4.01-3.91(m, 3H), 3.80- 3.78 (m, 5H), 3.66-3.64 (m, 2H), 3.39-3.33 (m, 4H),3.04-3.00 (m, 1H). 567.2 579 (3S,10S)-7-(4- acryloylpiperazin-1-yl)-10-(2,4- difluorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 1H), 7.18 (q, J = 6.4 Hz, 1H), 7.05-6.93 (m, 2H), 6.59 (dd, J = 10.4 Hz, 16.8 Hz, 1H), 6.37 (dd, J = 2.0 Hz,16.8 Hz, 1H), 5.78 (dd, J = 2.0 Hz, 10.4 Hz, 1H), 5.47-5.39 (m, 1H),4.00-3.92 (m, 3H), 3.81-3.78 (m, 5H), 3.69- 3.60 (m, 2H), 3.39 (s, 3H),3.37-3.33 (m, 1H), 3.04- 2.98 (m, 1H). 567.2 580 (3S,10S)-7-((2S,5R)-4-acryloyl- 2,5- dimethylpiperazin- 1-yl)-3-((4-cyclopropylpiperazin- 1-yl)methyl)-10- (2,4- difluorophenyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J = 6.0, 1H), 7.31-7.27 (m, 1H),7.16-7.10 (m, 2H), 6.73- 6.55 (m, 1H), 6.46-6.37 (m, 1H), 5.84-5.79 (m,1H), 5.44-5.42 (m, 1H), 5.13- 4.70 (m, 1.5H), 4.47-4.36 (m, 1H),4.11-3.70 (m, 3H), 3.52-3.32 (m, 1.5H), 3.11- 3.03 (m, 1H), 2.84-2.55(m, 10H), 1.52-1.43 (m, 7H), 0.57-0.42 (m, 4H). 689.3 581 (3S,10R)-7-((2S,5R)-4-acryloyl- 2,5- dimethylpiperazin- 1-yl)-3-((4-cyclopropylpiperazin- 1-yl)methyl)-10- (2,4- difluorophenyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.87 (s, 1H), 7.28-7.19 (m, 1H), 7.09- 6.98(m, 2H), 6.72-6.54 (m, 1H), 6.46-6.37 (m, 1H), 5.86-5.79 (m, 1H), 5.42-5.35 (m, 1H), 5.12-4.68 (m, 1.5H), 4.52-4.33 (m, 1H), 4.19-3.67 (m, 3H),3.51- 3.27 (m, 1.5H), 3.10-3.05 (m, 1H), 2.87-2.51 (m, 10H), 1.52-1.29(m, 7H), 0.59-0.44 (m, 4H). 689.3 587 (3S)-7-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4-difluorophenyl)- 3-((dimethylamino) methyl)-9- (trifluoromethyl)- 2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one

¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.29-7.28 (m, 1H), 7.10- 7.04(m, 1H), 6.66-6.59 (m, 1H), 6.44-6.38 (m, 1H), 5.77 (dd, J = 10.4 Hz,1.2 Hz, 1H), 5.42-5.36 (m, 1H), 4.68-4.64 (m, 2H), 4.18 (d, J = 13.2 Hz,2H), 3.55-3.50 (m, 1H), 3.41-3.31 (m, 2H), 3.07-3.00 (m, 1H), 2.91- 2.82(m, 1H), 2.45-2.32 (m, 7H), 1.62-1.59 (m, 3H), 1.50-1.46 (m, 3H). 642.2588 8′-((2S,5R)-4- Acryloyl-2,5- dimethylpiperazin- 1-yl)-11′-(2,4-difluorophenyl)-10′- (trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′-[1,4]thiazepino[2,3, 4-ij]quinazolin]-6′- one

¹H NMR (400 MHz, MeOH-d₄) δ 7.97 (d, J = 2.7 Hz, 1H), 7.30 (dq, J =13.7, 7.6 Hz, 1H), 7.11 (t, J = 8.3 Hz, 2H), 6.90-6.72 (m, 1H), 6.28(ddd, J = 16.7, 5.6, 2.0 Hz, 1H), 5.80 (ddd, J = 9.7, 7.2, 2.0 Hz, 1H),4.87-4.60 (m, 3H), 4.55-4.36 (m, 3H), 4.34- 3.69 (m, 4H), 3.62-3.40 (m,3H), 1.49-1.25 (m, 6H) 607.2 489 8′-(4- Acryloylpiperazin-1-yl-2,2,3,3,5,5,6,6- d₈)-11′-(2,4- difluorophenyl)-10′-(trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]-6′- one

¹H NMR (400 MHz, MeOH-d₄) δ 8.00 (s, 1H), 7.30 (q, J = 7.7 Hz, 1H), 7.11(t, J = 8.7 Hz, 2H), 6.80 (dd, J = 16.7, 10.6 Hz, 1H), 6.27 (dd, J =16.7, 1.9 Hz, 1H), 5.80 (dd, J = 10.6, 2.0 Hz, 1H), 4.82-4.54 (m, 2H),4.43 (d, J = 5.5 Hz, 2H), 3.61-3.46 (m, 2H), 3.23-3.11 (m, 2H) 587.2

Syntheses of Intermediates:

7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

Methyl 2-acetamido-4-chloro-5-iodobenzoate (2)

To a mixture of methyl 2-amino-4-chloro-5-iodobenzoate (50.00 g, 160.51mmol) in AcOH (500 mL) was added Ac₂O (19.66 g, 192.61 mmol). Themixture was stirred at 100° C. for 16 hours. After completion, themixture was cooled to room temperature, filtered and washed withPetroleum Ether (200 mL) to afford crude product (35 g, 62% yield) aswhite solid. MS (ESI) m/z: 353.9 [M+H]⁺.

Methyl 2-acetamido-4-chloro-5-(trifluoromethyl)benzoate (3)

To a mixture of methyl 2-acetamido-4-chloro-5-iodobenzoate (35.00 g,98.98 mmol) in DMF (350 mL) was added methyl2,2-difluoro-2-(fluorosulfonyl)acetate (70.09 g, 395.99 mmol), HMPA(70.98 g, 395.99 mmol) and CuI (15.05 g, 79.19 mmol). The mixture wasstirred at 90° C. under N₂ for 16 hours. After completion, the mixturewas poured into water (300 mL), extracted with EtOAc (3×200 mL). Thecombined organic phase was washed with brine (500 mL) and dried overNa₂SO₄. After filtration and concentration, the residue was purified bysilica gel column using a gradient of Petroleum Ether/EtOAc (100/1 to20/1) to afford desired product (25.00 g, 84% yield) as white solid. MS(ESI) m/z: 296.0 [M+H]⁺.

Methyl 2-amino-4-chloro-5-(trifluoromethyl)benzoate (4)

A mixture of methyl 2-acetamido-4-chloro-5-(trifluoromethyl)benzoate(20.00 g, 67.79 mmol) in HCl/MeOH (200 mL) was stirred at 70° C. for 2hours. The mixture was concentrated and a saturated aqueous solution ofNaHCO₃ (100 mL) was added. The resulting mixture was extracted withEtOAc (3×50 mL). The combined organic phase was washed with brine (100mL) and dried over Na₂SO₄. The solvent was removed in vacuo to affordthe crude product (18.00 g, crude) as a yellow solid. MS (ESI) m/z:254.0 [M+H]⁺

Methyl 2-amino-4-chloro-3-iodo-5-(trifluoromethyl)benzoate (5)

To a mixture of methyl 2-amino-4-chloro-5-(trifluoromethyl)benzoate(28.00 g, 110.23 mmol) in AcOH (280 mL) was added N-Iodosuccinimide(35.00 g, 143.29 mmol). The mixture was stirred at 50° C. for 16 hours.After completion, the mixture was poured into water (400 mL), extractedwith EtOAc (3×250 mL). The combined organic phases were washed withbrine (400 mL) and dried over Na₂SO₄. After filtration andconcentration, the residue was washed with PE (200 mL) to afford thecrude product (38.00 g, crude) as white solid. MS (ESI) m/z: 379.9[M+H]⁺

2-amino-4-chloro-3-iodo-5-(trifluoromethyl)benzoic acid (6)

To a solution of methyl2-amino-4-chloro-3-iodo-5-(trifluoromethyl)benzoate (25.00 g, 65.96mmol) in dioxane (200 mL) and water (200 mL) was added NaOH (5.28 g,131.92 mmol). The mixture was stirred at 90° C. for 3 hours. Aftercompletion, the mixture was poured into water (200 mL). The pH wasadjusted to 4˜5 and extracted with EtOAc (3×150 mL). The combinedorganic phase was washed with brine (300 mL) and dried over Na₂SO₄. Thesolvent was removed in vacuum to give2-amino-4-chloro-3-iodo-5-(trifluoromethyl)benzoic acid (23 g, crude) asyellow solid. MS (ESI) m/z: 365.9 [M+H]⁺

7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (7)

A mixture of 2-amino-4-chloro-3-iodo-5-(trifluoromethyl)benzoic acid (5g, 13.71 mmol) and urea (16.45 g, 274.2 mmol) was stirred at 200° C. for5 hours. After completion, the mixture was cooled to 80° C., water (100mL) was added to the solution and stirred for 1 hour. The mixture wasextracted with EtOAc (3×100 mL). The combined organic phase was washedwith brine (100 mL) and dried over Na₂SO₄. After filtration andconcentration, the residue was purified by silica gel column using amixture of Petroleum Ether/EtOAc (4/1) to afford the desired product(1.76 g, 33% yield) as a white solid. MS (ESI) m/z: 388.8 [M−H]⁻

11′-Chloro-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazoline]-6′,8′(7′H)-dione

[3-(Sulfanylmethyl)oxetan-3-yl]methanol (2)

Sodium hydrosulfide hydrate (0.209 g, 2.82 mmol, 1.1 equiv) wassuspended in anhydrous DMF (18 mL) and purged with argon.(3-(bromomethyl)oxetan-3-yl)methanol (0.3 mL, 2.57 mmol, 1.0 equiv) wasdissolved in anhydrous DMF (1 mL) in a separated vial and purged withargon. After 15 min, the solution of(3-(bromomethyl)oxetan-3-yl)methanol was added to the sodiumhydrosulfide suspension and the sealed vial was stirred at 45° C. for 2hours under argon. After, the reaction mixture was used in the next stepwithout characterization, work-up and purification (transferred to thevessel via syringe under argon atmosphere).

7-Chloro-8-({[3-(hydroxymethyl)oxetan-3-yl]methyl}sulfanyl)-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione(3)

To the vial containing7-chloro-8-iodo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione(1.0 g, 2.56 mmol, 1.0 equiv), K₂CO₃ (0.708 g, 5.12 mmol, 2.0 equiv) andcopper(I) iodide (0.488 g, 2.56 mmol, 1.0 equiv) was added. Solvents,isopropanol (40 mL) and ethylene glycol (40 mL) were added, and the vialwas purged with argon for 20 min. Next, crude[3-(sulfanylmethyl)oxetan-3-yl]methanol (0.344 g, 2.56 mmol, 1.0 equiv)was added to the reaction mixture via syringe under argon. The sealedvial was stirred at 80° C. overnight. According to UPLC, 15% of aryliodide remained. Next, additional freshly prepared[3-(sulfanylmethyl)oxetan-3-yl]methanol (0.138 g, 1.02 mmol, 0.4 equiv)was added. The reaction vial was purged with argon, sealed, and stirredovernight at 80° C. According to UPLC, 6% of aryl iodide remained. Next,the reaction mixture was concentrated, and the obtained oil wassuspended in a saturated aqueous NH₄Cl solution then stirred vigorouslyfor 20 min. The NH₄Cl solution was washed with EtOAc (3×100 mL), thenthe combined organic layers were washed with saturated aqueous NH₄Cl(1×100 mL) and dried over MgSO₄. The combined organic layers wereconcentrated by rotary evaporation. Purification by flash chromatography(Interchim puriFlash® F0120 silica gel column, MeOH/EtOAc=10:90, 60 min)afforded the title compound in poor purity. Re-purification bychromatography (Interchim, puriFlash® F0120 silica gel column) withEtOAc/acetone (1:1, 30 min) afforded the title compound as a white solid(0.535 g, 53% yield): ¹H NMR (300 MHz, DMSO-d₆) δ 11.86 (s, 1H), 10.58(s, 1H), 8.20 (s, 1H), 5.12 (t, J=5.4 Hz, 1H), 4.31 (s, 4H), 3.71 (d,J=5.1 Hz, 2H), 3.21 (s, 2H); LRMS-ESI (m/z) [M−H]⁻ calculated forC₁₄H₁₁ClF₃N₂O₄S 395.01, found 395.3.

11′-Chloro-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazoline]-6′,8′(7′H)-dione(4)

7-Chloro-8-({[3-(hydroxymethyl)oxetan-3-yl]methyl}sulfanyl)-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione(0.485 g, 1.222 mmol, 1.0 eq) and triphenylphosphine (1.28 g, 4.89 mmol,4.0 equiv) were dissolved in CH₂Cl₂ (anhydrous, 19.4 mL) and cooled to0° C. under argon over 15 minutes before dropwise addition ofdi-p-chlorobenzyl azodicarboxylate (Di-(4-chlorobenzyl)azodicarboxylate,1.80 g, 4.89 mmol, 4.0 equiv) in anhydrous CH₂Cl₂ over 1 min. Thereaction was allowed to stir at 0° C. under argon for 60 min. UPLC after60 min indicated no remaining starting material. The precipitated solidwas isolated by filtration under vacuum and washed with CH₂Cl₂. Thefiltrate was washed with saturated aqueous NH₄Cl. The layers wereseparated, and aqueous layer was washed with CH₂Cl₂ (2×25 mL). Thecombined organic layers were dried on a rotary evaporator. Purificationby column chromatography (Interchim puriFlash® F0080 silica gel column),eluting with EtOAc/hexanes (3:2, 60 min) afforded the title compound.Fractions with the desired product were evaporated to dryness by rotaryevaporation and the obtained material was suspended in mixture ofhexanes/EtOAc (5:3) and vigorously stirred. The solid was filtered offand dried under vacuum. The title compound was obtained as a white solid(340 mg, 67% yield): ¹H NMR (300 MHz, DMSO-d₆) δ 12.01 (s, 1H), 8.04 (s,1H), 7.46-7.40 (m, 2H), 5.08 (s, 2H), 4.39 (d, J=5.7 Hz, 2H), 3.72 (brs, 2H); ¹³C NMR (75 MHz, DMOS-d₆) δ 160.7, 156.3, 151.6, 145.1, 135.6,129.7, 128.6, 128.4, 123.0, 116.3, 77.5, 65.1, 51.4, 41.4, 37.6;LRMS-ESI (m/z) [M−H]⁻ calculated for C₁₄H₉ClF₃N₂O₃S 377.00, found376.84.

L. Example 448(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

(R)-7-(oxiran-2-ylmethyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-triazolo[4,3-a]pyrazine(2)

To a mixture of (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (7.9, 30.7mmol),3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine(7.0 g, 30.7 mmol) in acetonitrile (50 mL) was added potassium carbonate(12.7 g, 92.1 mmol) at 20° C. under nitrogen atmosphere. The mixture wasstirred under nitrogen atmosphere at room temperature for 20 hours.After completion, the mixture was concentrated. The residue was purifiedby silica gel column eluting with 2% methanol in dichloromethane toafford the product (6.2 g, 24.7 mmol) as a pale yellow oil. MS (ESI)m/z: 249.1 [M+H]⁺.

(R)-1-mercapto-3-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propan-2-ol(3)

To a mixture of(R)-7-(oxiran-2-ylmethyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine(6.1 g, 24.6 mmol) and tetrabutylammonium fluoride (30.7 mL, 30.7 mmol,1.0 M in tetrahydrofuran) in tetrahydrofuran (50 mL) was added1,1,1,3,3,3-hexamethyldisilathiane (5.4 g, 30.7 mmol) at 0° C. Themixture was stirred at room temperature for 2 hrs. After completion, themixture was poured into water (200 mL), extracted with ethyl acetate(3×200 mL). The combined organic phase was washed with brine (300 mL)and dried over anhydrous sodium sulfate. The mixture was concentratedand the residue was purified by silica gel column eluting withdichloromethane/methanol (50/1) to afford(R)-1-mercapto-3-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propan-2-ol(4.8 g, 17.0 mmol, 70% yield) as a pale yellow oil. MS (ESI) m/z: 283.1[M+H]⁺.

(R)-7-bromo-6-chloro-4-hydroxy-8-((2-hydroxy-3-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propyl)thio)quinazolin-2(1H)-one(4)

To a mixture of 7-bromo-6-chloro-4-hydroxy-8-iodoquinazolin-2(1H)-one(3.9 g, 10.0 mmol), potassium carbonate (4.14 g, 30.0 mmol),(R)-1-mercapto-3-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propan-2-ol(3.1 g, 11.0 mmol) and 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene(1.16 g, 2.0 mmol) in dioxane (128 mL) was addedtris(dibenzylideneacetone) dipalladium (0.92 g, 1.0 mmol). The mixturewas stirred at 55° C. under nitrogen atmosphere for 8 hrs. Aftercompletion, the mixture was filtered. The filtrate was concentrated andthe residue was purified by silica gel column chromatography (1-5%methanol in dichloromethane) to afford(R)-7-bromo-6-chloro-4-hydroxy-8-((2-hydroxy-3-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propyl)thio)quinazolin-2(1H)-one(3.5 g, 63% yield) as a yellow solid. MS (ESI) m/z: 557.0 [M+H]⁺.

(S)-10-bromo-9-chloro-7-hydroxy-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5)

To a mixture of(R)-7-bromo-6-chloro-4-hydroxy-8-((2-hydroxy-3-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propyl)thio)quinazolin-2(1H)-one(3.5 g, 6.3 mmol) and triphenylphosphine (2.0 g, 7.5 mmol) intetrahydrofuran (25 mL) was added diethyl azodicarboxylate (1.6 g, 7.5mmol) at 0° C. The mixture was stirred at 0° C. for 20 min. Aftercompletion, the mixture was concentrated. The residue was purified byflash chromatography column (C18, 5-95% acetonitrile in water) to afford(S)-10-bromo-9-chloro-7-hydroxy-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-oneas a pale yellow solid. MS (ESI): m/z: 539.0 [M+H]⁺.

(2R,5S)-tert-butyl4-((S)-10-bromo-9-chloro-5-oxo-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(6)

To a mixture of(S)-10-bromo-9-chloro-7-hydroxy-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(1.05 g, 2.0 mmol) and K₂CO₃ (828 mg, 6.0 mmol) in acetonitrile (10 mL)was added 2,4,6-triisopropylbenzene-1-sulfonyl chloride (906 mg, 3.0mmol). The mixture was stirred at 20° C. for 5 hours. To the mixture wasadded (2R,5S)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate (1.28 g,6.0 mmol) and stirred at 20° C. for another 3 hours. After completion,the mixture was concentrated under reduced pressure. The residue waspurified by silica gel column with 1-5% methanol in dichloromethane asgradient to afford desired product (580 mg, 0.80 mmol, 40% yield) asyellow solid. LC-MS m/z: 735.1 [M+H]⁺;

(2R,5S)-tert-butyl4-((3S)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-5-oxo-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(7)

To a mixture of (2R,5S)-tert-butyl4-((S)-10-bromo-9-chloro-5-oxo-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(210 mg, 0.28 mmol) and tripotassium orthophosphate (178 mg, 0.84 mmol)in 1,4-dioxane (5 mL) and water (1 mL) were added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (40.2 mg,0.05 mmol) and2-(5-chloro-2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(391 mg, 1.4 mmol). The mixture was stirred at 90° C. for 3 hours. Aftercompletion, the mixture was concentrated and the residue was purified bysilica gel column with 1-5% methanol in dichloromethane as gradient toafford (2R,5S)-tert-butyl4-((3S)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-5-oxo-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(203 mg, 0.25 mmol) as yellow solid. MS (ESI) m/z: 801.2 [M+H]⁺.

(3S)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a cooled mixture of (2R,5S)-tert-butyl4-((3S)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-5-oxo-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(203 mg, 0.25 mmol) in dichloromethane (3 ml) was added trifluoroaceticacid (1 mL) at 20° C. The reaction solution was stirred at roomtemperature for 1 hour. After completion, the mixture was concentrated.The residue was purified by silica gel column with 1-5% methanol indichloromethane as gradient to afford(3S)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(116 mg, 0.165 mmol) as a yellow solid. MS (ESI) m/z: 701.2 [M+H]⁺.

(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9)

To a mixture of(3S)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(116 mg, 0.165 mmol) and triethyl amine (100 mg, 1.0 mmol) indichloromethane (5 mL) was added acrylic anhydride (31 mg, 0.25 mmol) at0° C. The mixture was stirred at 0° C. for 1 h. After completion, themixture was poured into ice-water (50 mL) and extracted with ethylacetate (3×20 mL). The organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified by preparative High PerformanceLiquid Chromatography (10% to 95% acetonitrile in water) to afford theproduct as a white solid (43 mg, 0.06 mmol). ¹H NMR (400 MHz, CDCl₃) δ7.59-7.53 (m, 1H), 7.33-7.28 (m, 1H), 7.13-7.08 (m, 1H), 6.61-6.48 (m,1H), 6.40-6.32 (m, 1H), 5.79-5.75 (m, 1H), 5.54-5.38 (brs, 1H),5.03-4.96 (brs, 0.5H), 4.80-4.70 (m, 1H), 4.38-4.09 (m, 2.5H), 4.07-3.96(m, 3.5H), 3.71-3.65 (m, 2H), 3.30-3.08 (m, 5.5H), 2.96-2.91 (m, 1H),2.90-2.83 (m, 2H), 1.46-1.38 (m, 3H), 1.32-1.25 (m, 3H). MS (ESI) m/z:755.1 [M+H]⁺.

M. Example 462

(R)-7-(oxiran-2-ylmethyl)-2-oxa-7-azaspiro[3.5]nonane (2)

To a mixture of (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (5.9 g,22.8 mmol), 2-oxa-7-azaspiro[3.5]nonane oxalate (4.5 g, 20.7 mmol) inacetonitrile (60 mL) was added potassium carbonate (14.3 g, 103.6 mmol)at 0° C. under nitrogen atmosphere. The mixture was stirred at roomtemperature for 16 hours. After completion, the mixture was concentratedand the residue was purified by silica gel column eluting a mixture ofdichloromethane/methanol (20/1) to afford(R)-7-(oxiran-2-ylmethyl)-2-oxa-7-azaspiro[3.5]nonane (3.45 g, 91%yield) as a brown oil. MS (ESI) m/z: 180.1 [M+H]⁺.

(R)-1-mercapto-3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propan-2-ol (3)

To a mixture of (R)-7-(oxiran-2-ylmethyl)-2-oxa-7-azaspiro[3.5]nonane(3.74 g, 20.4 mmol) in tetrahydrofuran (70 mL) was added1,1,1,3,3,3-hexamethyldisilathiane (5.45 g, 30.6 mmol) andtetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 6.1 mL, 6.1 mmol)at 0° C. The resulting mixture was stirred at room temperature for 6hours. After completion, the mixture was concentrated and the residuewas purified by silica gel column eluting with dichloromethane/methanol(20/1) to afford(R)-1-mercapto-3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propan-2-ol (3.47 g,78% yield) as a brown oil. MS (ESI) m/z: 218.2 [M+H]⁺.

(R)-7-bromo-6-chloro-4-hydroxy-8-((2-hydroxy-3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propyl)thio)quinazolin-2(1H)-one(4)

To a solution of 7-bromo-6-chloro-8-iodoquinazoline-2,4(1H,3H)-dione(4.93 g, 12.3 mmol) in dioxane (50 mL) were added potassium carbonate(5.09 g, 36.8 mmol),(R)-1-mercapto-3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propan-2-ol (3.47 g,16.0 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (1.42 g,2.45 mmol) and tris(dibenzylideneacetone) dipalladium (1.12 g, 1.23mmol). The mixture was stirred at 50° C. under nitrogen atmosphere for16 hours. After completion, the mixture was concentrated and the residuewas purified by silica gel column eluting with dichloromethane/methanol(20/1) to afford(R)-7-bromo-6-chloro-4-hydroxy-8-((2-hydroxy-3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propyl)thio)quinazolin-2(1H)-one(4.47 g, 74% yield) as an orange solid. MS (ESI) m/z: 492.4 [M+H]⁺.

(S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-bromo-9-chloro-7-hydroxy-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5)

To a mixture of(R)-7-bromo-6-chloro-4-hydroxy-8-((2-hydroxy-3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propyl)thio)quinazolin-2(1H)-one(3.9 g, 7.95 mmol) and triphenylphosphoranylidene (4.16 g, 15.9 mmol) intetrahydrofuran (70 mL) was added diethyl azodicarboxylate (2.77 g, 15.9mmol). The mixture was stirred at room temperature for 2 hours. Aftercompletion, the mixture was poured into ice-water (100 mL) and extractedwith ethyl acetate (3×100 mL). The mixture was concentrated and theresidue was purified by silica gel column eluting withdichloromethane/methanol (50/1) to afford(S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-bromo-9-chloro-7-hydroxy-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(2.66 g, 71% yield) as a light yellow solid. MS (ESI) m/z: 474.4 [M+H]⁺.

(S)-tert-butyl4-((S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-bromo-9-chloro-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(6)

To a mixture of(S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-bromo-9-chloro-7-hydroxy-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(1.20 g, 2.54 mmol) and potassium carbonate (1.63 g, 25.40 mmol) inacetonitrile (100 mL) was added 2,4,6-triisopropylbenzenesulfonylchloride (2.30 g, 7.63 mmol) at 0° C. The mixture was stirred at 0° C.for 30 min and at 30° C. for 1 hour. After completion,(2R,5S)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate (1.53 g, 7.63mmol) was added into the reaction solution. The reaction mixture wasstirred at 0° C. for another 1 hour. After completion, the mixture waspoured into ice-water (300 mL) and extracted with ethyl acetate (3×200mL). The mixture was concentrated and the residue was purified by flashchromatography column (C18, acetonitrile/water=20% to 95%) to afford(S)-tert-butyl4-((S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-bromo-9-chloro-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(860 mg, 51% yield) as a pale-white solid. MS (ESI) m/z: 655.3 [M+H]⁺.

(S)-tert-butyl4-((S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-9-chloro-10-(4-fluorophenyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(7)

To a mixture of (S)-tert-butyl4-((S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-bromo-9-chloro-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(200 mg, 0.30 mmol) and tripotassium orthophosphate (325 mg, 1.53 mmol)in 1,4-dioxane (8 mL) and water (1 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (45 mg, 0.06mmol) and (4-fluorophenyl)boronic acid (214 mg, 1.52 mmol). The mixturewas stirred at 85° C. for 2 hours. After completion, the mixture wasdiluted with tetrahydrofuran (50 mL) and insoluble solid was filteredout. The mixture was concentrated and the residue was purified by silicagel column eluting with dichloromethane/methanol (50/1) to afford(S)-tert-butyl4-((S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-9-chloro-10-(4-fluorophenyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(214 mg, crude) as a light yellow oil. MS (ESI) m/z: 670.2 [M+H]⁺.

(S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-9-chloro-10-(4-fluorophenyl)-7-((S)-2-methylpiperazin-1-yl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a mixture of (S)-tert-butyl4-((S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-9-chloro-10-(4-fluorophenyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(214 mg, 0.32 mmol) in dichloromethane (3 mL) was added trifluoroaceticacid (1 mL). The mixture was stirred at room temperature for 30 min.After completion, the mixture was purified by silica gel column elutingwith dichloromethane/methanol (50/1) to afford(S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-9-chloro-10-(4-fluorophenyl)-7-((S)-2-methylpiperazin-1-yl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(130 mg, 71% yield) as a yellow solid. MS (ESI) m/z: 570.1 [M+H]⁺.

(S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10-(4-fluorophenyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9)

To a mixture of(S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-9-chloro-10-(4-fluorophenyl)-7-((S)-2-methylpiperazin-1-yl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(100 mg, 0.17 mmol) and triethylamine (54 mg, 0.51 mmol) indichloromethane (3 mL) was added acrylic anhydride (43 mg, 0.34 mmol) at0° C. The mixture was stirred at 0° C. for 1 hour. After completion, themixture was poured into ice-water (15 mL) and extracted with ethylacetate (3×15 mL). After concentration, the residue was purified bypreparative high performance liquid chromatography (20% to 95%acetonitrile in water as gradient) to afford the product (50 mg, 46%yield) as a light-yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.23-7.18 (m, 4H), 6.62-6.52 (m,1H), 6.36 (d, J=18.0 Hz, 1H), 5.77 (d, J=10.8 Hz, 1H), 5.29-5.27 (m,1H), 4.74-4.70 (m, 1H), 4.64 (m, 0.5H), 4.54-4.38 (m, 5H), 4.21-4.19 (m,0.5H), 3.96-3.95 (m, 0.5H), 3.81-3.77 (m, 0.5H), 3.62-3.49 (m, 2H),3.37-3.36 (m, 1H), 3.12-3.07 (m, 1H), 3.00-2.94 (m, 1H), 2.79-2.73 (m,1H), 2.65-2.55 (m, 2H), 2.49-2.47 (m, 1H), 2.43-2.35 (m, 2H), 1.88-1.75(m, 4H), 1.48-1.44 (m, 3H). MS (ESI) m/z: 624.1 [M+H]⁺.

N. Example 481(S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-3-((1-(2,2-difluoroethyl)azetidin-3-yl)methyl)-10-(4-fluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

(R)-dimethyl 2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)malonate (3)

To a mixture of sodium hydride (4.58 g, 190.87 mmol) in dimethylformide(208 mL) and tetrahydrofuran (104 mL) was added dimethyl malonate (21.6g, 163.6 mmol) dropwise at 0° C. under nitrogen atmosphere. The mixturewas allowed to warm up to room temperature for 1 hour, then(S)-4-(iodomethyl)-2,2-dimethyl-1,3-dioxolane (26.4 g, 109.07 mmol) wasadded dropwise. The mixture was heated to 80° C. and stirred overnight.After completion, the mixture was quenched with saturated aqueousammonium chloride solution, the aqueous layer was extracted with ethylacetate (2×500 mL). The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by silicagel column eluting with petroleum ether/ethyl acetate (50/1) to afford(R)-dimethyl 2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)malonate (18 g,67% yield) as pale yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ 4.16-4.10(m, 1H), 4.08-4.04 (m, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 3.63-3.56 (m,2H), 2.24-2.18 (m, 1H), 2.13-2.06 (m, 1H), 1.39 (s, 3H), 1.32 (s, 3H).

(R)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)propane-1,3-diol (4)

To a mixture of lithium aluminum hydride (4.07 g, 107.2 mmol) intetrahydrofuran (150 mL) was added dropwise (R)-dimethyl2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)malonate (8.8 g, 35.74 mmol)at 0° C. under nitrogen atmosphere. The mixture was stirred at 0° C. toroom temperature for 2 hours. After completion, the mixture was dilutedwith ether (100 mL) and cooled to 0° C., quenched with 4 mL water, then4 mL 15% sodium hydroxide solution and 12 mL water. The organic layerwas separated, dried over anhydrous sodium sulfate, filtered andconcentrated to afford(R)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)propane-1,3-diol (5.32 g,78% yield) as colorless oil, which was used to next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 4.25-4.18 (m, 1H), 4.09 (t,J=6.8 Hz, 1H), 3.77-3.68 (m, 4H), 3.53 (t, J=7.6 Hz, 1H), 1.93-1.87 (m,1H), 1.75-1.68 (m, 1H), 1.63-1.54 (m, 1H), 1.42 (s, 3H), 1.36 (s, 3H).

(R)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)propane-1,3-diylbis(4-methylbenzenesulfonate) (5)

To a solution of(R)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)propane-1,3-diol (5.32 g,27.96 mmol), 4-dimethylaminopyridine (444 mg, 3.63 mmol) and triethylamine (11.3 g, 111.84 mmol) in dichloromethane (50 mL) was added4-toluene sulfonyl chloride (18.98 g, 99.54 mmol) at 0° C. The mixturewas stirred at room temperature overnight. 200 mL water was added andextracted with dichloromethane (3×200 mL). The organic phase wasconcentrated and the residue was purified by silica gel column elutingwith petroleum ether/ethyl acetate=10/1 to afford(R)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)propane-1,3-diylbis(4-methylbenzenesulfonate) (10.16 g, 73% yield) as white solid. MS(ESI) m/z: 499.1 [M+H]⁺.

(R)-1-benzyl-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)azetidine (6)

To a solution of(R)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)propane-1,3-diylbis(4-methylbenzenesulfonate) (9.9 g, 19.8 mmol), phenylmethanamine (7.6mL, 69.44 mmol) in acetonitrile (90 mL) was addedN,N-diisopropylethylamine (7.6 mL, 43.69 mmol) at room temperature. Themixture was heated to reflux overnight. After completion, 200 mL waterwas added and extracted with dichloromethane (3×200 mL). The organicphase was concentrated and the residue was purified by silica gel columneluting with petroleum ether/ethyl acetate=1/1 to afford(R)-1-benzyl-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)azetidine (2.84g, 55% yield) as brown liquid. MS (ESI) m/z: 262.2 [M+H]⁺.

(R)-3-(1-benzylazetidin-3-yl)propane-1,2-diol (7)

To a mixture of(R)-1-benzyl-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)azetidine (2.84g, 10.88 mmol) in dichloromethane (28 mL) was added trifluoroacetic acid(14 mL) at room temperature. Then the mixture was stirred at roomtemperature for 2 hours. After completion, the mixture was concentratedand adjusted pH to 7˜8 with ammonia solution, then concentrated toafford (R)-3-(1-benzylazetidin-3-yl)propane-1,2-diol (9.4 g, crude) asyellow solid, which was used to next step without further purification.MS (ESI) m/z: 222.1 [M+H]⁺.

(R)-3-(azetidin-3-yl)propane-1,2-diol (8)

To a solution of (R)-3-(1-benzylazetidin-3-yl)propane-1,2-diol (4.577 g,20.7 mmol) in methanol (30 mL) was added palladium on charcoal (10%)(400 mg) at room temperature. The mixture was stirred under hydrogenprotection at 50° C. overnight. After completion, the mixture wasfiltered and concentrated to afford(R)-3-(azetidin-3-yl)propane-1,2-diol (4.2 g, crude) as yellow oil,which was used to next step without further purification. MS (ESI) m/z:132.1 [M+H]⁺.

(R)-benzyl 3-(2,3-dihydroxypropyl)azetidine-1-carboxylate (9)

To a mixture of (R)-3-(azetidin-3-yl)propane-1,2-diol (1.43 g, 10.88mol) and sodium carbonate (3.46 g, 32.64 mmol) in tetrahydrofuran (28mL) and water (28 mL) was added benzyl carbonochloridate (2.23 g, 13.06mol) slowly at 0° C. The mixture was stirred at 0° C. overnight. Aftercompletion, the mixture was extracted with ethyl acetate (100 mL), theorganic phase was washed with brine (100 mL×2), dried over anhydroussodium sulfate, filtered and concentrated. The residue was purified bysilica gel column eluting with dichloromethane/methanol=50/1 to afford(R)-benzyl 3-(2,3-dihydroxypropyl)azetidine-1-carboxylate (1.6 g, 55%yield for 2 steps) as colorless oil; MS (ESI) m/z: 266.1 [M+H]⁺.

(R)-benzyl 3-(2-hydroxy-3-(tosyloxy)propyl)azetidine-1-carboxylate (10)

To a solution of (R)-benzyl3-(2,3-dihydroxypropyl)azetidine-1-carboxylate (1.6 g, 6.03 mmol) andtriethyl amine (1.22 g, 12.06 mmol) in dichloromethane (30 mL) was added4-toluene sulfochloride (1.03 g, 5.43 mmol) at 0° C. The mixture wasstirred at room temperature for 4 hours. After completion, the mixturewas concentrated and the residue was purified by silica gel columneluting with dichloromethane/methanol (50/1) to afford the (R)-benzyl3-(2-hydroxy-3-(tosyloxy)propyl)azetidine-1-carboxylate (1.7 g, 67%yield) as pale yellow oil. MS (ESI) m/z: 420.1 [M+H]⁺.

(R)-benzyl 3-(3-(acetylthio)-2-hydroxypropyl)azetidine-1-carboxylate(11)

To a mixture of (R)-benzyl3-(2-hydroxy-3-(tosyloxy)propyl)azetidine-1-carboxylate (1.4 g, 3.34mmol) in acetone (20 mL) was added potassium ethanethioate (1.14 g,10.02 mmol). The mixture was stirred at 50° C. under nitrogen atmospherefor 1 hour. After completion, the mixture was filtered, and the filtratewas concentrated. The residue was purified by silica gel column elutingwith dichloromethane/methanol (60/1) to afford (R)-benzyl3-(3-(acetylthio)-2-hydroxypropyl)azetidine-1-carboxylate (800 mg, 74%yield) as colorless oil. MS (ESI) m/z: 324.1 [M+H]⁺.

(R)-benzyl3-(3-((7-(4-fluorophenyl)-4-hydroxy-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-8-yl)thio)-2-hydroxypropyl)azetidine-1-carboxylate(13)

The mixture of7-(4-fluorophenyl)-4-hydroxy-8-iodo-6-(trifluoromethyl)quinazolin-2(1H)-one(927 mg, 2.06 mmol), (R)-benzyl3-(3-(acetylthio)-2-hydroxypropyl)azetidine-1-carboxylate (800 mg, 2.48mmol), copper (I) iodide (197 mg, 1.03 mmol) and potassium carbonate(853 mg, 6.18 mmol) in ethane-1,2-diol (12 mL) and i-PrOH (12 mL) wasstirred under nitrogen atmosphere at 85° C. for 18 hours. Aftercompletion, ethyl acetate (200 mL) was added, the organic phase waswashed with water (2×150 mL), dried over anhydrous sodium sulfate,filtered and concentrated. The residue was purified by silica gel columnwith dichloromethane/ethyl acetate (3/1) to afford (R)-benzyl3-(3-((7-(4-fluorophenyl)-4-hydroxy-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-8-yl)thio)-2-hydroxypropyl)azetidine-1-carboxylate(320 mg, crude) as yellow solid. MS (ESI) m/z: 604.0 [M+H]⁺.

Benzyl3-(((3S)-10-(2,4-difluorophenyl)-7-hydroxy-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)azetidine-1-carboxylate(14)

To a mixture of (R)-benzyl3-(3-((7-(4-fluorophenyl)-4-hydroxy-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-8-yl)thio)-2-hydroxypropyl)azetidine-1-carboxylate(258 mg, 0.43 mmol) and triphenylphosphoranylidene (448 mg, 1.71 mmol)in tetrahydrofuran (80 mL) was added 1,2-bis[(4-chlorophenyl)methyl]ester (627 mg, 1.71 mmol) at 0° C. The mixture was stirred at 0° C. for45 min. After completion, the mixture was poured into ice-water (100 mL)and extracted with ethyl acetate (3×50 mL). The mixture was concentratedand the residue was purified by C18 column with 30-95% acetonitrile inwater as gradient to afford benzyl3-(((3S)-10-(2,4-difluorophenyl)-7-hydroxy-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)azetidine-1-carboxylate(117 mg, 47% yield) as white solid. MS (ESI) m/z: 586.0 [M+H]⁺.

(2R,5S)-tert-butyl4-((S)-3-((1-((benzyloxy)carbonyl)azetidin-3-yl)methyl)-10-(4-fluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(15)

To a solution of benzyl3-(((3S)-10-(2,4-difluorophenyl)-7-hydroxy-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)azetidine-1-carboxylate(75 mg, 0.128 mmol) and potassium carbonate (177 mg, 1.282 mmol) inacetonitrile (6 mL) was added 4-methylbenzenesulfonic anhydride (104 mg,0.320 mmol) in portions at room temperature. The mixture was stirred atroom temperature under nitrogen atmosphere for 5 hours. Aftercompletion, (2R,5S)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate (110mg, 0.512 mmol) was added into the reaction solution. The mixture wasstirred at room temperature for anther 0.5 hour. After completion, themixture was poured into ice-water (50 mL) and extracted with ethylacetate (3×50 mL), dried over Na₂SO₄ and concentrated. The residue waspurified by Flash chromatography column (C18, acetonitrile/water=30% to95%) to afford (2R,5S)-tert-butyl4-((S)-3-((1-((benzyloxy)carbonyl)azetidin-3-yl)methyl)-10-(4-fluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(60 mg, 60% yield) as a pale yellow solid. MS (ESI) m/z: 782.9 [M+H]⁺.

(2R,5S)-tert-butyl4-((S)-3-(azetidin-3-ylmethyl)-10-(4-fluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(16)

To solution of (2R,5S)-tert-butyl4-((S)-3-((1-((benzyloxy)carbonyl)azetidin-3-yl)methyl)-10-(4-fluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(60 mg, 0.077 mmol) in methanol (2 mL) was added palladium on charcoal(10%) (50 mg) at room temperature. The mixture was stirred underhydrogen at room temperature for 3 hours. After completion, the mixturewas filtered and concentrated to afford (2R,5S)-tert-butyl4-((S)-3-(azetidin-3-ylmethyl)-10-(4-fluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(47 mg, 94% yield) as pale yellow solid. MS (ESI) m/z: 648.8 [M+H]⁺.

(2R,5S)-tert-butyl4-((S)-3-((1-(2,2-difluoroethyl)azetidin-3-yl)methyl)-10-(4-fluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(17)

To solution of (2R,5S)-tert-butyl4-((S)-3-(azetidin-3-ylmethyl)-10-(4-fluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(47 mg, 0.07 mmol) and 1,1-difluoro-2-iodoethane (42 mg, 0.22 mmol) inacetonitrile (1 mL) was added potassium carbonate (30 mg, 0.22 mmol).The mixture was stirred at 90° C. under nitrogen protection overnight.After completed, the mixture was concentrated and purified by silica gelcolumn eluting with dichloromethane/ammonia-methanol (40/1) to affordthe (2R,5S)-tert-butyl4-((S)-3-((1-(2,2-difluoroethyl)azetidin-3-yl)methyl)-10-(4-fluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(40 mg, 78% yield) as pale yellow solid. MS (ESI) m/z: 712.8 [M+H]⁺.

(S)-3-((1-(2,2-difluoroethyl)azetidin-3-yl)methyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(18)

To a solution of (2R,5S)-tert-butyl4-((S)-3-((1-(2,2-difluoroethyl)azetidin-3-yl)methyl)-10-(4-fluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(40 mg, 0.056 mmol) in dichloromethane (1 mL) was added trifluoroaceticacid (1 mL) at 0° C. The reaction solution was stirred at roomtemperature for 1 hour. After completion, the mixture was concentratedand adjusted pH to 8˜9 by ammonia in methanol. The mixture wasconcentrated and purified by silica gel column eluting withdichloromethane/methanol (containing 0.5% ammonia) (20/1) to afford the(S)-3-((1-(2,2-difluoroethyl)azetidin-3-yl)methyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(33 mg, 96% yield) as pale yellow solid. MS (ESI) m/z: 612.7 [M+H]⁺.

(S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-3-((1-(2,2-difluoroethyl)azetidin-3-yl)methyl)-10-(4-fluorophenyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(19)

To a mixture of(S)-3-((1-(2,2-difluoroethyl)azetidin-3-yl)methyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(33 mg, 0.054 mmol) and triethyl amine (11 mg, 0.108 mmol) indichloromethane (1 mL) was added acrylic anhydride (7 mg, 0.054 mmol) at0° C. The mixture was stirred at 0° C. for 1 hour. After completion, themixture was poured into ice-water (20 mL) and extracted withdichloromethane (3×15 mL), dried over Ns₂SO₄, and concentrated. Theresidue was purified by preparative high Performance liquidchromatography (20% to 95% acetonitrile in water as gradient) to afford(S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-3-((1-(2,2-difluoroethyl)azetidin-3-yl)methyl)-10-(4-fluorophenyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(14 mg, 39% yield) as a white solid. MS (ESI) m/z: 666.3 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.84 (s, 1H), 7.26-7.25 (m, 1H), 7.21-7.17 (m,3H), 6.67-6.51 (m, 1H), 6.38 (t, J=15.6 Hz, 1H), 5.84-5.54 (m, 2H),5.27-5.26 (m, 1H), 5.06-5.01 (m, 0.5H), 4.84-4.83 (m, 0.5H), 4.71-4.70(m, 0.5H), 4.42-4.32 (m, 1.5H), 4.06-4.03 (m, 0.5H), 3.80-3.67 (m, 2H),3.59-3.52 (m, 2H), 3.33-3.29 (m, 0.5H), 3.06-2.97 (m, 3H), 2.88-2.84 (m,1H), 2.79-2.70 (m, 2H), 2.61-2.53 (m, 1H), 2.06 (t, J=6.8 Hz, 1H),1.47-1.38 (m, 6H).

O. Example 496(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

(R)-1-mercapto-3-methoxypropan-2-ol (2)

To a mixture of (S)-2-(methoxymethyl)oxirane (10.00 g, 113.6 mmol) intetrahydrofuran (150 mL) was added 1,1,1,3,3,3-hexamethyldisilathiane(30.33 g, 170.4 mmol) and tetrabutylammonium fluoride (1.0 M intetrahydrofuran, 34.1 mL, 34.1 mmol) at 0° C. The mixture was stirred atroom temperature for 2 hrs. After completion, the mixture was pouredinto water (300 mL), extracted with ethyl acetate (3×200 mL). Thecombined organic phase was washed with brine (300 mL) and dried overanhydrous sodium sulfate. After filtration and concentration, theresidue was purified by silica gel column eluting with petroleumether/ethyl acetate (3/1) to afford (R)-1-mercapto-3-methoxypropan-2-ol(17.0 g, crude) as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 3.86-3.82 (m, 1H), 3.49-3.46 (m, 1H),3.41-3.37 (m, 4H), 2.71-2.64 (m, 1H), 1.55-1.50 (m, 1H).

(R)-7-bromo-6-chloro-8-((2-hydroxy-3-methoxypropyl)thio)quinazoline-2,4(1H,3H)-dione(3)

To a solution of 7-bromo-6-chloro-8-iodoquinazoline-2,4(1H,3H)-dione(4.00 g, 9.97 mmol) in dioxane (100 mL) were added potassium carbonate(4.13 g, 29.91 mmol), (R)-1-mercapto-3-methoxypropan-2-ol (2.43 g, 19.94mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (1.15 g, 1.99mmol) and tris(dibenzylideneacetone) dipalladium (915 mg, 1.0 mmol). Themixture was stirred at 55° C. under nitrogen atmosphere for 18 hrs.After completion, the mixture was diluted with tetrahydrofuran (300 mL)and filtered. After concentration, the residue was purified by silicagel column chromatography eluting with dichloromethane/methanol (100/1)to afford(R)-7-bromo-6-chloro-8-((2-hydroxy-3-methoxypropyl)thio)quinazoline-2,4(1H,3H)-dione(3.15 g, 80% yield) as a white solid. MS (ESI) m/z: 387.0 [M+H]⁺.

(S)-10-bromo-9-chloro-3-(methoxymethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(4)

To a mixture of(R)-7-bromo-6-chloro-8-((2-hydroxy-3-methoxypropyl)thio)quinazoline-2,4(1H,3H)-dione(3.15 g, 8.16 mmol) and triphenylphosphoranylidene (4.28 g, 16.32 mmol)in tetrahydrofuran (160 mL) was added diethyl azodicarboxylate (2.84 g,16.32 mmol) at 0° C. The mixture was stirred at 0° C. for 45 min. Aftercompletion, the mixture was poured into ice-water (300 mL) and extractedwith ethyl acetate (3×500 mL). After concentration, the residue waspurified by Flash chromatography column (C18, acetonitrile/water=30% to95% as gradient) to afford(S)-10-bromo-9-chloro-3-(methoxymethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(1.84 g, 60% yield) as a white solid. MS (ESI) m/z: 378.0 [M+H]⁺.

(2R,5S)-tert-butyl4-((S)-10-bromo-9-chloro-3-(methoxymethyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(5)

To a mixture of(S)-10-bromo-9-chloro-3-(methoxymethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(1.84 g, 4.88 mmol) and potassium carbonate (6.73 g, 48.8 mmol) inacetonitrile (100 mL) was added 4-methylbenzenesulfonic anhydride (3.18g, 9.76 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min andat 30° C. for 1 hour. After completion, (2R,5S)-tert-butyl2,5-dimethylpiperazine-1-carboxylate (2.09 g, 9.76 mmol) was added intothe reaction solution. The reaction mixture was stirred at 0° C. for 1hour. After completion, the mixture was poured into ice-water (300 mL)and extracted with ethyl acetate (3×200 mL). After concentration, theresidue was purified by Flash chromatography column (C18,acetonitrile/water=20% to 95%) to afford (2R,5S)-tert-butyl4-((S)-10-bromo-9-chloro-3-(methoxymethyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(1.56 g, 56% yield) as a pale-white solid. MS (ESI) m/z: 575.1 [M+H]⁺.

(2R,5S)-tert-butyl4-((3S)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(6)

To a solution of (2R,5S)-tert-butyl4-((S)-10-bromo-9-chloro-3-(methoxymethyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(250 mg, 0.44 mmol) in 1,4-dioxane (8 mL) and water (1 mL) were addedtripotassium phosphate (373 mg, 1.76 mmol),2-(5-chloro-2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(724 mg, 2.64 mmol), and [1′1-bis(diphenylphosphino)ferrocene] dichloropalladiuM(II) (29 mg, 0.04 mmol). The mixture was stirred at 85° C.under nitrogen atmosphere for 10 hours. After completion, the mixturewas diluted with tetrahydrofuran (300 mL) and filtered. Afterconcentration, the residue was purified by silica gel columnchromatography eluting with a gradient of dichloromethane/methanol 100/1to 30/1 to afford (2R,5S)-tert-butyl4-((3S)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(260 mg, crude) as a yellow solid. MS (ESI) m/z: 641.6 [M+H]⁺.

(3S)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(7)

To a cooled mixture of (2R,5S)-tert-butyl4-((3S)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(260 mg, 0.44 mmol) in dichloromethane (5 ml) was added trifluoroaceticacid (2 mL) at 0° C. The reaction solution was stirred at roomtemperature for 1 h. After completion, the mixture was concentrated, theresidue was purified by column using a mixture ofdichloromethane/methanol (15:1) to afford(3S)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(160 mg, crude) as a yellow-brown solid. MS (ESI) m/z: 541.1 [M+H]⁺.

(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a mixture of(3S)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(130 mg, 0.24 mmol) and triethyl amine (49 mg, 0.48 mmol) indichloromethane (5 ml) was added acrylic anhydride (45 mg, 0.36 mmol) at0° C. The mixture was stirred at 0° C. for 1 h. After completion, themixture was poured into ice-water (50 mL) and extracted with ethylacetate (3×20 mL). After concentration, the residue was purified bypreparative High Performance Liquid Chromatography (20% to 95%acetonitrile in water) to afford(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(50 mg, 35% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.55-7.54(m, 1H), 7.33-7.29 (m, 1H), 7.11-7.06 (m, 1H), 6.66-6.50 (m, 1H), 6.37(t, J=15.6 Hz, 1H), 5.77 (t, J=7.6 Hz, 1H), 5.51-5.44 (m, 1H), 5.04-4.99(m, 0.6H), 4.85-4.69 (m, 1H), 4.42-4.30 (m, 1.4H), 4.07-4.01 (m, 0.5H),3.80-3.57 (m, 4H), 3.41-3.33 (m, 4.5H), 3.06-3.01 (m, 1H), 1.42-1.33 (m,6H). MS (ESI) m/z: 595.1 [M+H]⁺.

P. Example 498(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

(R)-2-((2-methoxyethoxy)methyl)oxirane (2)

To a mixture of 2-methoxyethanol (40.00 g, 525.66 mmol) intetrahydro-furan (3200 mL) was added sodium hydride (60% dispersed inmineral oil, 37.8 g, 946.20 mmol). The mixture was stirred at 0° C. for1 hour. Then (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (40.00 g,525.66 mmol) was added to the above solution, the mixture was stirred atroom temperature for 3 hours. After completion, the mixture was pouredinto water (3200 mL), extracted with ethyl acetate (3×1000 mL). Thecombined organic phase was washed with brine (1000 mL) and dried overanhydrous sodium sulfate. After filtration and concentration, theresidue was purified by silica gel column with petroleum ether to afford(R)-2-((2-methoxyethoxy)methyl) oxirane (27.00 g, crude) as colorlessoil.

¹H NMR (400 MHz, CDCl₃) δ 3.82-3.77 (m, 1H), 3.71-3.64 (m, 2H),3.58-3.54 (m, 2H), 3.46-3.38 (m, 4H), 3.18-3.16 (m, 1H), 2.81-2.78 (m,1H), 2.62-2.59 (m, 1H).

(R)-1-mercapto-3-(2-methoxyethoxy)propan-2-ol (3)

To a mixture of (R)-2-((2-methoxyethoxy)methyl)oxirane (27.00 g, 204.3mmol) in tetrahydrofuran (300 mL) was added1,1,1,3,3,3-hexamethyldisilathiane (40.10 g, 224.7 mmol) andtetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 15.17 mL, 224.7mmol) at 0° C. The mixture was stirred at room temperature for 2 hours.After completion, the mixture was poured into water (300 mL), extractedwith ethyl acetate (3×200 mL). The combined organic phase was washedwith brine (300 mL) and dried over anhydrous sodium sulfate. Afterfiltration and concentration, the residue was purified by silica gelcolumn eluting with a mixture of petroleum ether/ethyl acetate (3/1) toafford (R)-1-mercapto-3-(2-methoxyethoxy)propan-2-ol (7.2 g, 21% yield)as a colorless oil.

¹H NMR (400 MHz, CDCl₃) δ 3.86-3.83 (m, 1H), 3.69-3.65 (m, 2H),3.57-3.51 (m, 3H), 3.40-3.39 (m, 3H), 3.08-2.98 (m, 1H), 2.70-2.63 (m,2H), 1.53 (t, J=1.2 Hz, 1H).

(R)-7-chloro-4-hydroxy-8-((2-hydroxy-3-(2-methoxyethoxy)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(4)

To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (4.00 g, 10.24 mmol) in dioxane (100 mL) were added potassiumcarbonate (4.25 g, 30.73 mmol),(R)-7-chloro-4-hydroxy-8-((2-hydroxy-3-(2-methoxyethoxy)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(2.55 g, 15.37 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene(0.89 g, 1.54 mmol) and tris(dibenzylideneacetone) dipalladium (0.94 g,1.02 mmol). The mixture was stirred at 55° C. under nitrogen atmospherefor 18 hours. After completion, the mixture was diluted withtetrahydrofuran (300 mL) and filtered. After concentration, the residuewas purified by silica gel column chromatography eluting with a gradientof dichloromethane/methanol (100/1 to 8/1) to afford the title product(S)-10-chloro-7-hydroxy-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(2.15 g, 49% yield) as a white solid. MS (ESI) m/z: 429.0 [M+H]⁺.

(S)-10-chloro-7-hydroxy-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5)

To a mixture of(S)-10-chloro-7-hydroxy-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(2.09 g, 4.88 mmol) and triphenylphosphoranylidene (5.12 g, 19.51 mmol)in tetrahydrofuran (700 ml) was added 2,5-dichloro-2,5-dimethylhexane(7.16 g, 19.51 mmol) at 0° C. The mixture was stirred at 0° C. for 45min. After completion, the mixture was poured into ice-water (1500 mL)and extracted with ethyl acetate (3×500 mL). After concentration, theresidue was purified by Flash chromatography column (C18,acetonitrile/water=30% to 95%) to afford(S)-10-chloro-7-hydroxy-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2H-thiazino[2,3,4-ij] quinazolin-5(3H)-one(1.58 g, 79% yield) as a white solid. MS (ESI) m/z: 411.0 [M+H]⁺.

(2R,5S)-tert-butyl4-((S)-10-chloro-3-((2-methoxyethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(6)

To a mixture of (S)-10-chloro-7-hydroxy-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(1.58 g, 3.85 mmol) and potassium carbonate (5.32 g, 38.49 mmol) inacetonitrile (100 mL) was added 4-methylbenzenesulfonic anhydride (3.77g, 11.55 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min andat 30° C. for 1 hour. After completion, (2R,5S)-tert-butyl2,5-dimethylpiperazine-1-carboxylate (3.30 g, 15.40 mmol) was added intothe reaction solution. The reaction mixture was stirred at 0° C. for 1hour. After completion, the mixture was poured into ice-water (300 mL)and extracted with ethyl acetate (3×200 mL). After concentration, theresidue was purified by Flash chromatography column (C18,acetonitrile/water=20% to 95%) to afford (2R,5S)-tert-butyl4-((S)-10-chloro-3-((2-methoxyethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(1.97 g, 85% yield) as a yellow solid. MS (ESI) m/z: 607.1 [M+H]⁺.

(2R, 5S)-tert-butyl 4-((3S)-10-(2,4-difluorophenyl)-3-((2-methoxyethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(7)

To a solution of (2R,5S)-tert-butyl4-((S)-10-chloro-3-((2-methoxyethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(350 mg, 0.58 mmol) in 1,4-dioxane (6 mL) and water (1 mL) were addedtripotassium phosphate (734 mg, 3.46 mmol), (2,4-difluorophenyl) boronicacid (456 mg, 2.89 mmol), and chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(45 mg, 0.058 mmol). The mixture was stirred at 85° C. under nitrogenatmosphere for 4 hours. After completion, the mixture was diluted withtetrahydrofuran (300 mL) and filtered. After concentration, the residuewas purified by silica gel column chromatography using a gradient ofdichloromethane/methanol (100/1 to 8/1) to afford (2R,5S)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-3-((2-methoxyethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(2.15 g, 49% yield) as a white solid. MS (ESI) m/z: 685.1 [M+H]⁺.

(3S)-10-(2,4-difluorophenyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a cooled mixture of (2R,5S)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-3-((2-methoxyethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(410 mg, 0.58 mmol) in dichloromethane (5 ml) was added trifluoroaceticacid (5 mL) at 0° C. The reaction solution was stirred at roomtemperature for 1 hour. After completion, the mixture was concentrated,the residue was purified by column eluting with dichloromethane/methanol(5/1) to afford (3S)-10-(2,4-difluorophenyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(701 mg, crude) as a yellow-brown solid. MS (ESI) m/z: 585.1 [M+H]⁺.

(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9)

To a mixture of (3S)-10-(2,4-difluorophenyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(655 mg, 0.54 mmol) and triethyl amine (164 mg, 1.62 mmol) indichloromethane (10 ml) was added acrylic anhydride (68 mg, 0.54 mmol)at 0° C. The mixture was stirred at 0° C. for 1 hour. After completion,the mixture was poured into ice-water (50 mL) and extracted with ethylacetate (3×20 mL). After concentration, the residue was purified bypreparative High Performance Liquid Chromatography (20% to 95%acetonitrile in water) to afford(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(113 mg, 33% yield) as a white solid. MS (ESI) m/z: 639.1 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.87-7.83 (m, 1H), 7.19-7.15 (m, 1H),7.03-6.95 (m, 2H), 6.67-6.51 (m, 1H), 6.37 (t, J=14.4 Hz, 1H), 5.78 (t,J=9.2 Hz, 1H), 5.50-5.36 (m, 1H), 5.14-5.00 (m, 0.6H), 4.78-4.66 (m,1H), 4.45-4.41 (m, 1H), 4.41-4.34 (m, 0.4H), 4.16-4.08 (m, 0.6H),3.78-3.63 (m, 6H), 3.52 (t, J=4.8 Hz, 2H), 3.41-3.38 (m, 1H), 3.35 (s,3H), 3.26-3.22 (m, 0.4H), 3.05-2.95 (m, 1H), 1.50-1.44 (m, 6H).

Q. Example 500(3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

(1S,4S)-5-((R)-oxiran-2-ylmethyl)-2-oxa-5-azabicyclo[2.2.1]heptanes (2)

To a mixture of (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (38.2 g,147.5 mmol) and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (20.0 g, 147.5mmol) in acetonitrile (300 mL) was added potassium carbonate (61 g,442.5 mmol) at 0° C. under nitrogen atmosphere. The mixture was stirredat 0° C. for 16 hours. After completion, the mixture was concentratedand the residue was purified by silica gel column eluting with a mixtureof dichloromethane/methanol (20/1) to afford the product (15.0 g, 66%yield) as a yellow oil. MS (ESI) m/z: 156.1 [M+H]⁺.

(R)-1-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3-mercaptopropan-2-ol(3)

To a mixture of(1S,4S)-5-((R)-oxiran-2-ylmethyl)-2-oxa-5-azabicyclo[2.2.1]heptane (6 g,38.7 mmol) in tetrahydrofuran (60 mL) were added1,1,1,3,3,3-hexamethyldisilathiane (8.9 g, 50.3 mmol) andtetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 11.6 mL, 11.6mmol) at 0° C. The mixture was stirred at room temperature for 2 hours.After completion, the mixture was poured into water (60 mL), extractedwith ethyl acetate (3×100 mL). The organic phase was washed with brine(200 mL) and dried over anhydrous sodium sulfate. After filtration andconcentration, the residue was purified by silica gel column elutingwith a mixture of dichloromethane/methanol (50/1) to afford(R)-1-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3-mercaptopropan-2-ol(2.6 g, 35% yield) as a colorless oil. MS (ESI) m/z: 190.1 [M+H]⁺.

8-(((R)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-hydroxypropyl)thio)-7-bromo-6-chloro-4-hydroxyquinazolin-2(1H)-one(4)

To a solution of 7-bromo-6-chloro-4-hydroxy-8-iodoquinazolin-2(1H)-one(1.00 g, 2.5 mmol) in dioxane (30 mL) were added potassium carbonate(1.38 g, 10.0 mmol),(R)-1-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3-mercaptopropan-2-ol(742.5 mg, 3.75 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene(289 mg, 0.5 mmol) and tris(dibenzylideneacetone) dipalladium (421 mg,0.46 mmol). The mixture was stirred at 55° C. under nitrogen atmospherefor 16 hours. After completion, the mixture was diluted withtetrahydrofuran (100 mL) and filtered. The filtrate was concentrated andthe residue was purified by silica gel column chromatography using agradient of dichloromethane/methanol (100/1 to 20/1) to afford8-(((R)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-hydroxypropyl)thio)-7-bromo-6-chloro-4-hydroxyquinazolin-2(1H)-one(560 mg, 48% yield) as a yellow solid. MS (ESI) m/z: 462.1 [M+H]⁺.

(S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-bromo-9-chloro-7-hydroxy-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5)

To a mixture of8-(((R)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-hydroxypropyl)thio)-7-bromo-6-chloro-4-hydroxyquinazolin-2(1H)-one(560 mg, 1.21 mmol) and triphenylphosphine (579 mg, 1.5 mmol) intetrahydrofuran (200 mL) was added diethyl azodicarboxylate (810 mg, 1.5mmol) at 0° C. The mixture was stirred at 0° C. for 45 min. Aftercompletion, the mixture was poured into ice-water (50 mL) and extractedwith ethyl acetate (3×50 mL). The mixture was concentrated and theresidue was purified by flash chromatography column (C18,acetonitrile/water=30% to 95%) to afford(S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-bromo-9-chloro-7-hydroxy-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(500 mg, 85% yield) as a white solid. MS (ESI): m/z: 444.3 [M+H]⁺.

(2R,5S)-tert-butyl4-((S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-bromo-9-chloro-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(6)

To a mixture of(S)-3-((1R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-9-bromo-10-chloro-7-hydroxy-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(500 mg, 1.12 mmol) and potassium carbonate (1.5 g, 11.2 mmol) inacetonitrile (20 mL) was added benzenesulphonyl chloride (678 mg, 2.24mmol) at 25° C. The mixture was stirred at 25° C. for 1 hour. Then(2R,5S)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate (720 mg, 3.36mmol) was added and the resulting mixture was stirred at 25° C. for 1hour. After completion, the mixture was poured into ice-water (30 mL)and extracted with ethyl acetate (3×30 mL). After concentration, theresidue was purified by Flash chromatography column (C18,acetonitrile/water=20% to 95%) to afford (2R,5S)-tert-butyl4-((S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-bromo-9-chloro-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(233 mg, 33% yield) as a yellow solid. MS (ESI) m/z: 640.6 [M+H]⁺.

(2R,5S)-tert-butyl4-((3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(7)

To a solution of (2R,5S)-tert-butyl4-((S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-bromo-9-chloro-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(233 mg, 0.36 mmol) in 1,4-dioxane (5 mL) and water (1 mL), tripotassiumphosphate (230 mg, 1.08 mmol), (5-chloro-2,4-difluorophenyl)boronic acid(794 mg, 2.88 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (53 mg,0.072 mmol) were added. The mixture was stirred at 85° C. under nitrogenatmosphere for 4 hours. After completion, the mixture was diluted withtetrahydrofuran (50 mL) and the insoluble solid was removed byfiltration. The mixture was concentrated and the residue was purified bysilica gel column chromatography (dichloromethane/methanol=100/1 to 30/1as gradient) to afford (2R,5S)-tert-butyl4-((3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(180 mg, 75% yield) as a yellow oil. MS (ESI) m/z: 708.7 [M+H]⁺.

(2R,5S)-tert-butyl4-((3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(8)

To a cooled mixture of (2R,5S)-tert-butyl4-((3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(180 mg, 0.25 mmol) in dichloromethane (5 mL) was added trifluoroaceticacid (1 mL) at 0° C. The reaction solution was stirred at roomtemperature for 1 hour. After completion, the mixture was concentratedand the residue was purified by silica gel column chromatography using amixture of dichloromethane/methanol (15/1) to afford (2R,5S)-tert-butyl4-((3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(120 mg, 85% yield) as a yellow solid. MS (ESI) m/z: 608.5 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.65-7.64 (m, 1H), 7.32-7.26 (m, 1H),7.12-7.06 (m, 1H), 5.37-5.27 (m, 1H), 4.40-4.37 (m, 1H), 4.19-4.18 (m,1H), 3.92-3.88 (m, 1H), 3.72-3.55 (m, 4H), 3.47-3.45 (m, 2H), 3.34-3.30(m, 2H), 3.04-2.92 (m, 4H), 2.89-2.78 (m, 3H), 1.80-1.69 (m, 3H),1.45-1.26 (m, 3H).

(3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9)

To a mixture of (2R,5S)-tert-butyl4-((3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(120 mg, 0.20 mmol) and triethylamine (41 mg, 0.40 mmol) indichloromethane (5 mL) was added acrylic anhydride (25 mg, 0.20 mmol) at0° C. The mixture was stirred at 0° C. for 1 hour. After completion, themixture was poured into ice-water (15 mL) and extracted with ethylacetate (3×15 mL). After concentration, the residue was purified bypreparative high performance liquid chromatography (20% to 95%acetonitrile in water) to afford(3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(48 mg, 37% yield) as a yellow solid. MS (ESI) m/z: 662.1 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 7.54-7.52 (m, 1H), 7.32-7.25 (m, 1H), 7.12-7.06 (m,1H), 6.66-6.50 (m, 1H), 6.41-6.33 (m, 1H), 5.79-5.75 (m, 1H), 5.28-5.24(m, 1H), 5.01-4.70 (m, 2H), 4.40-4.26 (m, 2H), 4.02-3.90 (m, 2H),3.69-3.55 (m, 4H), 3.46-3.29 (m, 1H), 3.03-2.86 (m, 5H), 1.77-1.65 (m,2H), 1.52-1.33 (m, 6H).

R. Example 518(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

(S)-2-((methoxymethoxy)methyl)oxirane (2)

To a mixture of (R)-oxiran-2-ylmethanol (15 g, 202.7 mmol) andN,N-diisopropylethylamine (52.3 g, 405.4 mmol) in dichloromethane (200mL) was added bromo(methoxy)methane (32.7 g, 263.5 mmol) at 0° C. Themixture was allowed to warm to room temperature and stirred for 5 hours.After completion, the mixture was poured into dichloromethane (300 mL),washed with water (3×200 mL). The organic phase was washed with brine(100 mL) and dried over anhydrous sodium sulfate. After filtration andconcentration, the residue was purified by silica gel column withpetroleum ether to afford (S)-2-((methoxymethoxy)methyl)oxirane (25.00g, crude) as colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 4.66 (d, J=1.2 Hz,2H), 3.79 (dd, J=11.6 Hz, 3.2 Hz, 1H), 3.51 (dd, J=11.6 Hz, 2.0 Hz, 1H),3.38 (s, 3H), 3.20-3.16 (m, 1H), 2.83-2.80 (m, 1H), 2.64 (dd, J=5.2 Hz,2.8 Hz, 1H).

(R)-1-mercapto-3-(methoxymethoxy)propan-2-ol (3)

To a mixture of (S)-2-((methoxymethoxy)methyl)oxirane (10 g, 84.7 mmol)in tetrahydrofuran (250 mL) was added 1,1,1,3,3,3-hexamethyldisilathiane(16.63 g, 93.2 mmol) and tetrabutylammonium fluoride (1.0 M intetrahydrofuran, 25 mL, 25 mmol) at 0° C. The mixture was stirred atroom temperature for 2 hours. After completion, the mixture concentratedunder reduced pressure, the residue was purified by silica gel columneluting with petroleum ether/ethyl acetate=4/1 to afford(R)-1-mercapto-3-(methoxymethoxy)propan-2-ol (2 g, 16% yield) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 4.66 (s, 2H), 3.85-3.82 (m,1H), 3.69-3.60 (m, 2H), 3.39 (s, 3H), 2.88 (brs, 1H), 2.71-2.65 (m, 2H),1.51 (t, J=8.8 Hz, 1H).

(R)-7-chloro-4-hydroxy-8-((2-hydroxy-3-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(4)

To a solution of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (1.86 g,4.77 mmol) in dioxane (40 mL) were added potassium carbonate (1.32 g,9.54 mmol), (R)-1-mercapto-3-(methoxymethoxy)propan-2-ol (1.09 g, 7.15mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (413 mg, 0.72mmol) and Tris(dibenzylideneacetone) dipalladium (439 g, 0.48 mmol). Themixture was stirred at 60° C. under nitrogen atmosphere for 18 hours.After completion, the mixture was concentrated under reduced pressure.The residue was purified by silica gel column chromatography elutingwith dichloromethane/methanol=60/1 to afford(R)-7-chloro-4-hydroxy-8-((2-hydroxy-3-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(1.33 g, 67% yield) as pale yellow solid. MS (ESI) m/z: 415.0 [M+H]⁺.

(S)-10-chloro-7-hydroxy-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5)

To a mixture of(R)-7-chloro-4-hydroxy-8-((2-hydroxy-3-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(1.33 g, 3.21 mmol) and triphenylphosphoranylidene (3.37 g, 12.85 mmol)in tetrahydrofuran (500 ml) was added 1,2-bis[(4-chlorophenyl)methyl]ester (4.71 g, 12.85 mmol) at 0° C. The mixture was stirred at 0° C. for45 min. After completion, the mixture was poured into ice-water (200 mL)and extracted with ethyl acetate (200 mL×3). Concentrated and theresidue was purified by C18 with gradient of 30-95% acetonitrile inwater to afford(S)-10-chloro-7-hydroxy-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(1.1 g, 87% yield) as a pale yellow solid. MS (ESI) m/z: 397.0 [M+H]⁺.

(S)-tert-butyl4-((S)-10-chloro-3-((methoxymethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(6)

To a mixture of(S)-10-chloro-7-hydroxy-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(1.1 g, 2.78 mmol) and potassium carbonate (3.84 g, 27.8 mmol) inacetonitrile (50 mL) was added 4-methylbenzenesulfonic anhydride (1.81g, 5.56 mmol) at 0° C. The mixture was stirred at room temperature for 4hours. After completion, (S)-tert-butyl 3-methylpiperazine-1-carboxylate(1.95 g, 8.33 mmol) was added into the reaction solution. The reactionmixture was stirred at 0° C. for 1 hour. After completion, the mixturewas poured into ice-water (200 mL) and extracted with ethyl acetate (100mL×3). After concentration, the residue was purified by C18 column withgradient of 20-95% acetonitrile in water to afford (S)-tert-butyl4-((S)-10-chloro-3-((methoxymethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(1 g, 59% yield) as a pale yellow solid. MS (ESI) m/z: 613.1 [M+H]⁺.

(3S)-tert-butyl4-((3S)-10-(5-chloro-2,4-difluorophenyl)-3-((methoxymethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(7)

To a solution of (S)-tert-butyl4-((S)-10-chloro-3-((methoxymethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(250 mg, 0.408 mmol) in 1,4-dioxane (6 mL) and water (1 mL) were addedtripotassium phosphate (260 mg, 1.224 mmol),(5-chloro-2,4-difluorophenyl)boronic acid (560 mg, 2.04 mmol), andChloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(32 mg, 0.04 mmol). The mixture was stirred at 80° C. under nitrogenatmosphere for 4 hours. After completion, the mixture was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography eluting with dichloromethane/methanol=50/1 to afford(3S)-tert-butyl4-((3S)-10-(5-chloro-2,4-difluorophenyl)-3-((methoxymethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(398 mg, crude) as a yellow solid. MS (ESI) m/z: 725.7 [M+H]⁺.

(3S)-10-(5-chloro-2,4-difluorophenyl)-3-((methoxymethoxy)methyl)-7-((S)-2-methylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a mixture of (3S)-tert-butyl4-((3S)-10-(5-chloro-2,4-difluorophenyl)-3-((methoxymethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(398 mg, 0.55 mmol) in methanol (15 ml) was added palladium on charcoal(10%) (148 mg). The reaction solution was stirred at room temperatureunder hydrogen atmosphere for 1 hour. After completion, the mixture wasfiltered and concentrated, the residue was purified by column(dichloromethane/methanol=5:1) to afford(3S)-10-(2,4-difluorophenyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(701 mg, impure) as a yellow-brown solid. MS (ESI) m/z: 591.5 [M+H]⁺.

(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9)

To a mixture of (3S)-10-(2,4-difluorophenyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(272 mg, 0.46 mmol) and triethyl amine (93 mg, 0.92 mmol) indichloromethane (5 ml) was added acrylic anhydride (70 mg, 0.55 mmol) at0° C. The mixture was stirred at 0° C. for 1 hour. After completion, themixture was poured into ice-water (30 mL) and extracted withdichloromethane (30 mL×3). After concentration, the residue was purifiedby preparative High Performance Liquid Chromatography with gradient of20% to 95% acetonitrile in water to afford(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(73.6 mg, 25% yield) as a white solid. MS (ESI) m/z: 645.2 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.78 (s, 1H), 7.31-7.24 (m, 1H), 7.10-7.04 (m,1H), 6.67-6.50 (m, 1H), 6.38 (dd, J=16.8 Hz, 2.0 Hz, 1H), 5.79 (d,J=10.4 Hz, 1H), 5.50-5.38 (m, 1H), 4.80-4.62 (m, 3H), 4.59-4.26 (m, 2H),4.06-3.92 (m, 0.5H), 3.90-3.74 (m, 2.5H), 3.67-3.47 (m, 1.5H), 3.46-3.33(m, 4.5H), 3.17-2.96 (m, 2H), 1.61-1.44 (m, 3H).

S. Example 5318′-((2S,5R)-4-Acryloyl-2,5-dimethylpiperazin-1-yl)-11′-(2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one

tert-Butyl(2S,6R)-4-(11′-chloro-6′-oxo-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-8′-yl)-2,6-dimethylpiperazine-1-carboxylate(2)

Compound 1 (30 mg, 0.08 mmol, 1 equiv) was dissolved in MeCN (1.6 mL,0.05 M) under a N₂ atmosphere in a 5 mL microwave vial. Potassiumcarbonate (33 mg, 0.24 mmol, 3 equiv) was added to the reaction mixtureand the reaction mixture was briefly sonicated. p-Toluenesulfonicanhydride (52 mg, 0.16 mmol, 2 equiv) was added to the vial at roomtemperature. The reaction mixture was stirred for 21 hours and reached65% conversion (determined by LC-MS). Next, tert-butyl(2R,6S)-2,6-dimethylpiperazine-1-carboxylate (34 mg, 0.16 mmol, 2 equiv)and K₂CO₃ (22 mg, 0.16 mmol, 2 equiv) were added to the vial and stirredfor 30 min at room temperature. The intermediate was determined to befully consumed by LC-MS and the solvent was removed by rotaryevaporation. The mixture was transferred with CH₂Cl₂ to a separatoryfunnel, washed with saturated aqueous NH₄Cl (20 mL), extracted withCH₂Cl₂ (2×50 mL), dried over Na₂SO₄, and filtered. The solvent wasremoved by rotary evaporation. The crude material was partially purifiedby flash column chromatography using an Isolera One Biotage instrument(0-6% MeOH/CH₂Cl₂, 10 g column, 0% (5 CV), 0-6% (15 CV), 6% (5 CV)), toprovide compound 2 (44 mg, impure) as a yellow solid. This impurematerial was used as is in the subsequent step: TLC (5% MeOH/CH₂Cl₂)R_(f)=0.43; LRMS-ESI (m/z) [M+H]⁺ calculated for C₂₅H₃₁ClF₃N₄O₄S 575.17,found 575.2.

tert-Butyl(2S,6R)-4-(11′-(2,4-difluorophenyl)-6′-oxo-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-8′-yl)-2,6-dimethylpiperazine-1-carboxylate(3)

Compound 2 (44 mg, impure ˜0.08 mmol, 1 equiv) was dissolved in1,4-dioxane and H₂O (1.3 mL, 0.3 mL, respectively, 0.05 M). Theresulting mixture was purged with N₂ for 30 min prior to the addition ofRuPhos Pd G4 (6.8 mg, 0.008 mmol, 10 mol %), K₃PO₄ (51 mg, 0.24 mmol, 3equiv), and (2,4-difluorophenyl)boronic acid (63 mg, 0.4 mmol, 5 equiv).The microwave vial was fitted with a crimp-top cap, bubbled with N₂ foran additional 5 min, and placed on a heated block at 80° C. Theresulting reaction mixture was homogenous and orange. After 1 h, thevial was removed from the heating block, allowed to cool, and thesolvent was removed by rotary evaporation (full conversion determined byLC-MS). The crude material was partially purified by flash columnchromatography using an Isolera One Biotage instrument (0-6%MeOH/CH₂Cl₂, 10 g column, 0% (5 CV), 0-6% (15 CV), 6% (5 CV)) to affordthe desired product (3) as a brown oil (38 mg). The material was used asis in the subsequent step: TLC (3% MeOH/CH₂Cl₂) R_(f)=0.19; LRMS-ESI(m/z) [M+H]⁺ calculated for C₃₁H₃₄F₅N₄O₄S 653.22, found 653.3.

8′-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-11′-(2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one(4)

Standard deBoc and acrylation conditions: 0.054 mmol scale, 8.7 mgoff-white solid, 27% yield:

¹H NMR (400 MHz, MeOH-d₄) δ 8.16 (s, 1H), 7.31 (q, J=7.6 Hz, 1H), 7.11(t, J=8.6 Hz, 2H), 6.84 (dd, J=16.7, 10.6 Hz, 1H), 6.29 (dd, J=16.7, 2.0Hz, 1H), 5.80 (dd, J=10.5, 2.0 Hz, 1H), 5.37-4.95 (m, 2H), 4.87-4.50 (m,4H), 4.43 (dd, J=6.3, 1.6 Hz, 2H), 4.25 (d, J=13.5 Hz, 2H), 3.65-3.36(m, 4H), 1.52 (d, J=6.6 Hz, 3H), 1.48 (d, J=6.8 Hz, 3H); LRMS-ESI (m/z)[M+H]⁺ calculated for C₂₉H₂₈F₅N₄O₃S 607.18, found 607.3.

T. Example 5888′-((2S,5R)-4-Acryloyl-2,5-dimethylpiperazin-1-yl)-11′-(2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one

The title compound was synthesized using similar procedures describedfor Example 531.

¹H NMR (400 MHz, MeOH-d₄) δ 7.97 (d, J=2.7 Hz, 1H), 7.30 (dq, J=13.7,7.6 Hz, 1H), 7.11 (t, J=8.3 Hz, 2H), 6.90-6.72 (m, 1H), 6.28 (ddd,J=16.7, 5.6, 2.0 Hz, 1H), 5.80 (ddd, J=9.7, 7.2, 2.0 Hz, 1H), 4.87-4.60(m, 3H), 4.55-4.36 (m, 3H), 4.34-3.69 (m, 4H), 3.62-3.40 (m, 3H),1.49-1.25 (m, 6H); LRMS-ESI (m/z) [M+H]⁺ calculated for C₂₉H₂₈F₅N₄O₃S607.18, found 607.2.

U. Example 5898′-(4-Acryloylpiperazin-1-yl-2,2,3,3,5,5,6,6-d₈)-11′-(2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one

The title compound was synthesized via similar methods described forExample 531.

¹H NMR (400 MHz, MeOH-d₄) δ 8.00 (s, 1H), 7.30 (q, J=7.7 Hz, 1H), 7.11(t, J=8.7 Hz, 2H), 6.80 (dd, J=16.7, 10.6 Hz, 1H), 6.27 (dd, J=16.7, 1.9Hz, 1H), 5.80 (dd, J=10.6, 2.0 Hz, 1H), 4.82-4.54 (m, 2H), 4.43 (d,J=5.5 Hz, 2H), 3.61-3.46 (m, 2H), 3.23-3.11 (m, 2H); LRMS-ESI (m/z)[M+H]⁺ calculated for C₂₇H₁₆D₈F₅N₄O₃S 587.20, found 587.2.

V. Examples 546 and 547(3S,10S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-oneand(3S,10R)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

(R)-1-mercapto-3-methoxypropan-2-ol (2)

To a mixture of (S)-2-(methoxymethyl)oxirane (10.00 g, 113.6 mmol) intetrahydrofuran (150 mL) was added 1,1,1,3,3,3-hexamethyldisilathiane(30.33 g, 170.4 mmol) and tetrabutylammonium fluoride (1.0 M intetrahydrofuran, 34.1 mL, 34.1 mmol) at 0° C. The mixture was stirred atroom temperature for 2 hours. After completion, the mixture was pouredinto water (300 mL), extracted with ethyl acetate (3×200 mL). Thecombined organic phase was washed with brine (300 mL) and dried overanhydrous sodium sulfate. After filtration and concentration, theresidue was purified by silica gel column eluting with petroleumether/ethyl acetate (3/1) to afford (R)-1-mercapto-3-methoxypropan-2-ol(17.0 g, crude) as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 3.86-3.82 (m, 1H), 3.49-3.46 (m, 1H),3.41-3.37 (m, 4H), 2.71-2.64 (m, 1H), 1.55-1.50 (m, 1H).

(R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(3)

To a solution of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (4.00 g,10.24 mmol) in dioxane (100 mL) were added potassium carbonate (4.25 g,30.73 mmol), (R)-1-mercapto-3-methoxypropan-2-ol (2.50 g, 20.48 mmol),4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (0.89 g, 1.54 mmol) andtris(dibenzylideneacetone) dipalladium (0.94 g, 1.02 mmol). The mixturewas stirred at 55° C. under nitrogen atmosphere for 18 hours. Aftercompletion, the mixture was diluted with tetrahydrofuran (300 mL) andfiltered. After concentration, the residue was purified by silica gelcolumn chromatography with a gradient of dichloromethane/methanol=100/1to 30/1 to afford(R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(3.15 g, 80% yield) as a white solid. MS (ESI) m/z: 385.0 [M+H]⁺.

(S)-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(4)

To a mixture of(R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(3.15 g, 8.20 mmol) and triphenylphosphoranylidene (4.29 g, 16.40 mmol)in tetrahydrofuran (160 mL) was added diethyl azodicarboxylate (2.85 g,16.40 mmol) at 0° C. The mixture was stirred at 0° C. for 45 min. Aftercompletion, the mixture was poured into ice-water (300 mL) and extractedwith ethyl acetate (500 mL×3). After concentration, the residue waspurified by Flash chromatography column (C18, acetonitrile/water=30% to95%) to afford(S)-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(2.10 g, 70% yield) as a white solid. MS (ESI): m/z: 367.0 [M+H]⁺.

(2S,6R)-tert-butyl4-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(5)

To a mixture of(S)-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(200 mg, 0.55 mmol) and potassium carbonate (759 mg, 5.50 mmol) inacetonitrile (25 mL) was added 4-methylbenzenesulfonic anhydride (534mg, 1.65 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min and30° C. for 1 hour. After completion, (2S,6R)-tert-butyl2,6-dimethylpiperazine-1-carboxylate (353 mg, 1.65 mmol) was added intothe reaction solution. The reaction mixture was stirred at 0° C. for 1hour. After completion, the mixture was poured into ice-water (300 mL)and extracted with ethyl acetate (3×200 mL). After concentration, theresidue was purified by Flash chromatography column (C18,acetonitrile/water=20% to 95%) to afford (2S,6R)-tert-butyl4-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(230 mg, 74% yield) as a pale-white solid. MS (ESI) m/z: 563.5 [M+H]⁺.

(2S,6R)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6)

To a solution of (2S,6R)-tert-butyl4-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(230 mg, 0.41 mmol) in 1,4-dioxane (8 mL) and water (1 mL) were addedtripotassium phosphate (348 mg, 1.64 mmol), (2,4-difluorophenyl)boronicacid (385 mg, 2.45 mmol), and Chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(64 mg, 0.08 mmol). The mixture was stirred at 85° C. under nitrogenatmosphere for 4 hours. After completion, the mixture was diluted withtetrahydrofuran (300 mL) and filtered. Then After concentration, theresidue was purified by silica gel column chromatography with a gradientof dichloromethane/methanol (100/1 to 30/1) to afford (2S,6R)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(220 mg, crude) as a yellow solid. MS (ESI) m/z: 641.6 [M+H]⁺.

(3S)-10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(7)

To a mixture of (2S,6R)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(220 mg, 0.34 mmol) in dichloromethane (5 ml) was added trifluoroaceticacid (2 mL) at 0° C. The reaction solution was stirred at roomtemperature for 1 hour. After completion, the mixture was concentrated.The residue was purified by column chromatography (eluting withdichloromethane/methanol (15:1) to afford(3S)-10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(140 mg, 76% yield) as a yellow solid. MS (ESI) m/z: 541.6 [M+H]⁺.

(3S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a mixture of(3S)-10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(120 mg, 0.22 mmol) and triethyl amine (44 mg, 0.44 mmol) indichloromethane (5 ml) was added acrylic anhydride (42 mg, 0.33 mmol) at0° C. The mixture was stirred at 0° C. for 1 hour. After completion, themixture was poured into ice-water (50 mL) and extracted with ethylacetate (20 mL×3). The organic layer was dried over Na₂SO₄ and filtered.After concentration, the residue was purified by preparative HighPerformance Liquid Chromatography (20% to 95% acetonitrile in water) toafford(3S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(100 mg, 76% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s,1H), 7.17 (q, J=8.0 Hz, 1H), 7.06-6.93 (m, 2H), 6.62 (dd, J=10.4 Hz,16.8 Hz, 1H), 6.40 (dd, J=2.0 Hz, 16.8 Hz, 1H), 5.77 (dd, J=2.0 Hz, 10.4Hz, 1H), 5.48-5.41 (m, 1H), 4.79-4.53 (m, 2H), 4.21-4.16 (m, 2H),3.69-3.59 (m, 2H), 3.37-3.30 (m, 6H), 3.05-2.99 (m, 1H), 1.62 (d, J=6.8Hz, 3H), 1.47 (d, J=6.8 Hz, 3H). MS (ESI) m/z: 595.6 [M+H]⁺.

The above racemate (72 mg) was dissolved in EtOH (5 mL) and separated bychiral supercritical fluid chromatography (separation condition: Column:Chiralpak AD-H 5 μm 20×250 mm; Mobile Phase: CO₂:EtOH=70:30 at 25mL/min; Temp: 25° C.; Wavelength: 254 nm) to afford two atropisomers ofthe title compounds P1 (30.0 mg, 41% yield, 100% de), and P2 (35.0 mg,48% yield, 100% de); Chiral HPLC Analytical: on CHIRALPAK® AD-H wasusing 5 μm 4.6×250 mm column, Mobile Phase: CO₂:EtOH=70:30 at 2.5mL/min; Temp: 25° C.; Wavelength: 254 nm).

P1: ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.18 (q, J=8.0 Hz, 1H),7.05-6.93 (m, 2H), 6.62 (dd, J=6.0 Hz, 16.4 Hz, 1H), 6.40 (dd, J=1.6 Hz,16.4 Hz, 1H), 5.77 (dd, J=1.6 Hz, 10.4 Hz, 1H), 5.48-5.45 (m, 1H),4.70-4.60 (m, 1H), 4.22-4.17 (m, 2H), 3.74-3.60 (m, 3H), 3.39-3.31 (m,6H), 3.03-2.99 (m, 1H), 1.63-1.61 (m, 3H), 1.47 (d, J=7.2 Hz, 3H);Chiral SFC fraction 1: d.e.=100%, Rt=4.14 min.

P2: ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.18 (q, J=7.6 Hz, 1H),7.04-6.94 (m, 2H), 6.62 (dd, J=10.0 Hz, 16.8 Hz, 1H), 6.40 (dd, J=2.0Hz, 16.8 Hz, 1H), 5.77 (dd, J=2.0 Hz, 10.8 Hz, 1H), 5.46-5.42 (m, 1H),4.73-4.61 (m, 1H), 4.21-4.16 (m, 2H), 3.74-3.64 (m, 3H), 3.40-3.30 (m,6H), 3.03 (dd, J=2.4 Hz, 13.2 Hz, 1H), 1.63-1.61 (m, 3H), 1.47 (d, J=7.2Hz, 3H); Chiral SFC fraction 1: d.e.=100%, Rt=4.29 min.

W. Example 560(3S)-3-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

(1S,4S)-5-((R)-oxiran-2-ylmethyl)-2-oxa-5-azabicyclo[2.2.1]heptanes (2)

To a mixture of (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (38.2 g,147.5 mmol), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (20.0 g, 147.5mmol) in acetonitrile (300 mL) was added potassium carbonate (61 g,442.5 mmol) at 0° C. under nitrogen atmosphere. The mixture was stirredunder nitrogen atmosphere at room temperature for 16 hours. Aftercompletion, the mixture was concentrated. The residue was purified bysilica gel column eluting with dichloromethane/methanol (20/1) to affordthe product (15.0 g, 66% yield) as a yellow oil. MS (ESI) m/z: 156.1[M+H]⁺.

(R)-1-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3-mercaptopropan-2-ol(3)

To a mixture of(1S,4S)-5-((R)-oxiran-2-ylmethyl)-2-oxa-5-azabicyclo[2.2.1]heptane (6 g,38.7 mmol) in tetrahydrofuran (60 mL) were added1,1,1,3,3,3-hexamethyldisilathiane (8.9 g, 50.3 mmol) andtetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 11.6 mL, 11.6mmol) at 0° C. The mixture was stirred at room temperature for 2 hours.After completion, the mixture was poured into water (60 mL), extractedwith ethyl acetate (3×100 mL). The organic phase was washed with brine(200 mL) and dried over anhydrous sodium sulfate. After filtration andconcentration, the residue was purified by silica gel column elutingwith dichloromethane/methanol (50/1) to afford(R)-1-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3-mercaptopropan-2-ol(2.6 g, 35% yield) as a colorless oil. MS (ESI) m/z: 190.1 [M+H]+.

8-(((R)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-hydroxypropyl)thio)-7-chloro-4-hydroxy-6-(trifluoromethyl)quinazolin-2(1H)-one(4)

To a solution of7-chloro-4-hydroxy-8-iodo-6-(trifluoromethyl)quinazolin-2(1H)-one (4.00g, 9.10 mmol) in dioxane (100 mL) were added potassium carbonate (3.70g, 27.3 mmol),(R)-1-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3-mercaptopropan-2-ol(2.57 g, 13.6 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene(1.05 g, 1.82 mmol) and tris(dibenzylideneacetone) dipalladium (0.823 g,0.91 mmol). The mixture was stirred at 55° C. under nitrogen atmospherefor 8 hours. After completion, the mixture was diluted withtetrahydrofuran (200 mL) and filtered. The filtrate was concentrated andthe residue was purified by silica gel column chromatography(dichloromethane/methanol=100/1 to 20/1 as gradient) to afford8-(((R)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-hydroxypropyl)thio)-7-chloro-4-hydroxy-6-(trifluoromethyl)quinazolin-2(1H)-one(4.00 g, 97% yield) as a yellow solid. MS (ESI) m/z: 452.5 [M+H]⁺.

(S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-chloro-7-hydroxy-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5)

To a mixture of8-(((R)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-hydroxypropyl)thio)-7-chloro-4-hydroxy-6-(trifluoromethyl)quinazolin-2(1H)-one(3.50 g, 7.70 mmol) and triphenylphosphine (3.00 g, 11.6 mmol) intetrahydrofuran (50 mL) was added diethyl azodicarboxylate (2.60 g, 15.4mmol) at 0° C. The mixture was stirred at 0° C. for 45 min. Aftercompletion, the mixture was poured into ice-water (200 mL) and extractedwith ethyl acetate (200 mL×3). After concentration, the residue waspurified by flash chromatography column (C18, acetonitrile/water=30% to95%) to afford(S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-chloro-7-hydroxy-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(3.14 g, 70% yield) as a white solid. MS (ESI) m/z: 434.4 [M+H]⁺.

(2S,6R)-tert-butyl4-((S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-chloro-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6)

To a mixture of(S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-chloro-7-hydroxy-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(700 mg, 1.60 mmol) and potassium carbonate (2.20 g, 16.0 mmol) inacetonitrile (20 mL) was added 4-methylbenzenesulfonic anhydride (782mg, 2.40 mmol) at 25° C. The mixture was stirred at 25° C. for 3 hours.(2R,6S)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (684 mg, 3.20mmol) was added into the reaction solution. The reaction mixture wasstirred at 25° C. for 1 hour. After completion, the mixture was pouredinto ice-water (50 mL) and extracted with ethyl acetate (3×50 mL). Themixture was concentrated and the residue was purified by flashchromatography column (C18, acetonitrile/water=20% to 95%) to afford(2S,6R)-tert-butyl4-((S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-chloro-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(800 mg, 80% yield) as a yellow solid. MS (ESI) m/z: 630.6 [M+H]⁺.

(2S,6R)-tert-butyl4-((3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(7)

To a solution of (2S,6R)-tert-butyl4-((S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-chloro-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(300 mg, 0.476 mmol) in 1,4-dioxane (10 mL) and water (2 mL) were addedtripotassium phosphate (404 mg, 1.90 mmol), (2,4-difluorophenyl)boronicacid (602 mg, 3.81 mmol), and chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(74 mg, 0.095 mmol). The mixture was stirred at 85° C. under nitrogenatmosphere for 4 hours. After completion, the mixture was diluted withtetrahydrofuran (50 mL) and filtered. The filtrate was concentrated andthe residue was purified by silica gel column chromatography withgradient of dichloromethane/methanol=100/1 to 30/1 to afford(2S,6R)-tert-butyl4-((3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(252 mg, 75% yield) as a yellow solid. MS (ESI) m/z: 708.4 [M+H]⁺.

(3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a mixture of (2S,6R)-tert-butyl4-((3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(252 mg, 0.36 mmol) in dichloromethane (5 mL) was added trifluoroaceticacid (1 mL) at 0° C. The reaction solution was stirred at roomtemperature for 1 hour. After completion, the mixture was concentratedand the residue was purified by silica gel column chromatography elutingwith dichloromethane/methanol (15:1) to afford(3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(185 mg, 85% yield) as a yellow solid. MS (ESI) m/z: 608.1 [M+H]+.

(3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9)

To a mixture of(3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(160 mg, 0.26 mmol) and triethyl amine (40 mg, 0.39 mmol) indichloromethane (5 mL) was added acrylic anhydride (40 mg, 0.31 mmol) at0° C. The mixture was stirred at 0° C. for 1 hour. After completion, themixture was poured into ice-water (50 mL) and extracted with ethylacetate (3×20 mL). The mixture was concentrated and the residue waspurified by preparative high performance liquid chromatography (20% to95% acetonitrile in water) to afford(3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(103 mg, 59% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.21-7.14 (m, 1H), 7.06-6.93 (m,2H), 6.66-6.59 (m, 1H), 6.43-6.38 (m, 1H), 5.77 (d, J=12.0 Hz, 1H),5.28-5.24 (m, 1H), 4.74-4.60 (m, 2H), 4.43-4.37 (m, 1H), 4.19 (d, J=13.6Hz, 2H), 3.91-3.84 (m, 1H), 3.69-3.31 (m, 5.5H), 2.99-2.85 (m, 4.5H),1.75-1.66 (m, 2H), 1.60-1.58 (m, 3H), 1.49-1.41 (m, 3H). MS (ESI) m/z:662.1 [M+H]⁺.

X. Example 576 and 577

(R)-7-(oxiran-2-ylmethyl)-2-oxa-7-azaspiro[3.5]nonane (2)

To a mixture of (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (5.9 g,22.8 mmol), 2-oxa-7-azaspiro[3.5]nonane oxalate (4.5 g, 20.7 mmol) inacetonitrile (60 mL) was added potassium carbonate (14.3 g, 103.6 mmol)at 0° C. The mixture was stirred under nitrogen atmosphere at roomtemperature for 16 hours. After completion, the mixture was concentratedand the residue was purified by silica gel column eluting withdichloromethane/methanol (20/1) to afford(R)-7-(oxiran-2-ylmethyl)-2-oxa-7-azaspiro[3.5]nonane (3.45 g, 91%yield) as a brown oil. MS (ESI) m/z: 180.1 [M+H]⁺.

(R)-1-mercapto-3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propan-2-ol (3)

To a mixture of (R)-7-(oxiran-2-ylmethyl)-2-oxa-7-azaspiro[3.5]nonane(3.74 g, 20.4 mmol) in tetrahydrofuran (70 mL) was added1,1,1,3,3,3-hexamethyldisilathiane (5.45 g, 30.6 mmol) andtetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 6.1 mL, 6.1 mmol)at 0° C. The mixture was stirred at room temperature for 6 hours. Aftercompletion, the mixture was concentrated and the residue was purified bysilica gel column eluting with dichloromethane/methanol (20/1) to afford(R)-1-mercapto-3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propan-2-ol (3.47 g,78% yield) as a brown oil. MS (ESI) m/z: 218.2 [M+H]⁺.

(R)-7-chloro-4-hydroxy-8-((2-hydroxy-3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(4)

To a solution of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2.0 g,4.59 mmol) in dioxane (50 mL) were added potassium carbonate (2.5 g,18.36 mmol),(R)-1-mercapto-3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propan-2-ol (1.5 g,6.88 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (526 mg,0.9 mmol) and tris(dibenzylideneacetone) dipalladium (421 mg, 0.45mmol). The mixture was stirred at 50° C. under nitrogen atmosphere for16 hours. After completion, the mixture was concentrated and the residuewas purified by flash chromatography column (C18, acetonitrile/water=30%to 95%) to afford(R)-7-chloro-4-hydroxy-8-((2-hydroxy-3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(2.16 g, 98% yield) as a yellow solid. MS (ESI) m/z: 480.4 [M+H]⁺.

(S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-chloro-7-hydroxy-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5)

To a mixture of(R)-7-chloro-4-hydroxy-8-((2-hydroxy-3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(2.16 g, 4.5 mmol) and triphenylphosphoranylidene (1.77 g, 6.75 mmol) intetrahydrofuran (800 mL) was added diethyl azodicarboxylate (1.18 g,6.75 mmol). The mixture was stirred at room temperature for 2 hours.After completion, the mixture was poured into ice-water (100 mL) andextracted with ethyl acetate (100 mL×3). The organic layer was driedover Na₂SO₄. After concentration, the residue was purified by flashchromatography column (C18, acetonitrile/water=20% to 95%) to afford(S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-chloro-7-hydroxy-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(1.45 g, 70% yield) as a white solid. MS (ESI) m/z: 462.1 [M+H]⁺.

(2S,6R)-tert-butyl4-((S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-chloro-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6)

To a mixture of(S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-chloro-7-hydroxy-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(700 mg, 1.52 mmol) and potassium carbonate (2.1 g, 15.2 mmol) inacetonitrile (60 mL) was added 4-methylbenzenesulfonic anhydride (992mg, 3.04 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minuteand at room temperature for 2 hours. After completion,(2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (977 mg, 4.56mmol) was added into the reaction solution. The mixture was stirred atroom temperature for 1 hour. After completion, the mixture was pouredinto ice-water (50 mL) and extracted with ethyl acetate (3×50 mL). Afterconcentration, the residue was purified by Flash chromatography column(C18, acetonitrile/water=20% to 95%) to afford (2S,6R)-tert-butyl4-((S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-chloro-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(710 mg, 71% yield) as a yellow solid. MS (ESI) m/z: 658.7 [M+H]⁺.

(2S,6R)-tert-butyl4-((3S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(7)

To a mixture of (2S,6R)-tert-butyl4-((S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-chloro-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(200 mg, 0.30 mmol) and tripotassium orthophosphate (194 mg, 0.91 mmol)in 1,4-dioxane (5 mL) and water (1 mL) was addedChloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(24 mg, 0.03 mmol) and (2,4-difluorophenyl)boronic acid (480 mg, 3.04mmol). The mixture was stirred at 80° C. for 4 hours. After completion,the mixture was purified by silica gel column eluting withdichloromethane/methanol (20/1) to afford the (2S,6R)-tert-butyl4-((3S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(215 mg, 96% yield) as a yellow solid. MS (ESI) m/z: 736.9 [M+H]⁺.

(3S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a mixture of(3S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(215 mg, 0.29 mmol) in dichloromethane (3 mL) was added trifluoroaceticacid (1 mL). The mixture was stirred at room temperature for 2 hours.After completion, the mixture was concentrated and the residue waspurified by silica gel column eluting with dichloromethane/methanol(20/1) to afford the(3S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(120 mg, 65% yield) as a yellow solid. MS (ESI) m/z: 636.7 [M+H]⁺.

(3S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9)

To a mixture of(3S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(100 mg, 0.16 mmol) and triethylamine (32 mg, 0.32 mmol) indichloromethane (8 mL) was added acrylic anhydride (20.1 mg, 0.16 mmol)at 0° C. The mixture was stirred at 0° C. for 2 hours. After completion,the mixture was purified by preparative high performance liquidchromatography (20% to 95% acetonitrile in water as gradient) to affordthe product (50 mg, 46% yield) as a light yellow solid. MS (ESI) m/z:690.1 [M+H]⁺.

The above racemate (50 mg, 0.07 mmol) was dissolved in ethanol (5 mL)and separated by chiral supercritical fluid chromatography (separationcondition: Column: AD-H 5 μm 20*250 mm; Mobile Phase: CO₂:IPA=60:40 at15 mL/min; Temp: 25° C.; Wavelength: 254 nm) to afford two atropisomersof the title compounds (P1: 15.6 mg with 100% de and P2: 18.4 mg with100% de); Chiral SFC Analytical condition: on AD-H was using 5 μm4.6×250 mm column, Mobile Phase: CO₂:IPA=60:40 at 1 mL/min; Temp: 25°C.; Wavelength: 254 nm).

P1: ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.21-7.15 (m, 1H), 7.06-6.94(m, 2H), 6.65-6.59 (m, 1H), 6.43-6.38 (m, 1H), 5.79-5.76 (dd, J=10.4 Hz,1.6 Hz, 1H), 5.37-5.35 (m, 1H), 4.72-4.65 (m, 2H), 4.46-4.32 (m, 4H),4.20-4.17 (m, 2H), 3.48-3.30 (m, 3H), 3.00-2.96 (m, 1H), 2.76-2.66 (m,1H), 2.65-2.51 (m, 2H), 2.47-2.28 (m, 3H), 1.82-1.81 (m, 4H), 1.61-1.60(m, 3H), 1.48-1.47 (m, 3H); Chiral SFC fraction 1: d.e.=100%, Rt=5.82min.

P2: ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.23-7.14 (m, 1H), 7.04-6.95(m, 2H), 6.65-6.59 (m, 1H), 6.42-6.38 (m, 1H), 5.78-5.76 (dd, J=10.4 Hz,1.6 Hz, 1H), 5.32-5.31 (m, 1H), 4.66-4.57 (m, 2H), 4.44-4.32 (m, 4H),4.20-4.16 (m, 2H), 3.44-3.30 (m, 3H), 3.07-2.98 (m, 1H), 2.76-2.71 (m,1H), 2.68-2.52 (m, 2H), 2.49-2.27 (m, 3H), 1.80-1.71 (m, 4H), 1.62-1.60(m, 3H), 1.49-1.42 (m, 3H); Chiral SFC fraction 2: d.e.=99.8%, Rt=6.76min.

Y. Example 580 and 581

(R)-benzyl 4-(oxiran-2-ylmethyl)piperazine-1-carboxylate (2)

To a mixture of(S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (25.0 g,96.5 mmol) and benzyl piperazine-1-carboxylate (19.3 g, 75.8 mmol) inacetonitrile (150 mL) was added potassium carbonate (24.0 g, 176 mmol)at 0° C. The mixture was stirred under nitrogen atmosphere at roomtemperature for 22 hours. After completion, the mixture was concentratedand the residue was purified by silica gel column eluting withdichloromethane/methanol (50/1) to afford (R)-benzyl4-(oxiran-2-ylmethyl)piperazine-1-carboxylate (24.5 g, crude) as a lightyellow oil. MS (ESI) m/z: 277.4 [M+H]⁺.

(R)-benzyl 4-(3-hydroxy-2-mercaptopropyl)piperazine-1-carboxylate (3)

To a mixture of (R)-benzyl 4-(oxiran-2-ylmethyl)piperazine-1-carboxylate(24.5 g, 88.7 mmol) in tetrahydrofuran (300 mL) were added1,1,1,3,3,3-hexamethyldisilathiane (17.4 g, 97.5 mmol) andtetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 26.7 m, 26.7mmol) at 0° C. The mixture was stirred at room temperature for 2 hours.After completion, the mixture was poured into water (300 mL), extractedwith ethyl acetate (3×200 mL). The organic phase was washed with brine(300 mL) and dried over anhydrous sodium sulfate. After filtration andconcentration, the residue was purified by silica gel column elutingwith dichloromethane/methanol (50/1) to afford (R)-benzyl4-(3-hydroxy-2-mercaptopropyl)piperazine-1-carboxylate (20.8 g, 76%yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.31 (m, 5H),5.13 (s, 2H), 3.80-3.78 (m, 1H), 3.54-3.50 (m, 4H), 3.39 (s, 1H),2.66-2.57 (m, 4H), 2.46-2.40 (m, 4H), 1.57-1.52 (m, 1H). MS (ESI) m/z:311.5 [M+H]⁺.

(R)-benzyl4-(3-((7-chloro-4-hydroxy-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-8-yl)thio)-2-hydroxypropyl)piperazine-1-carboxylate(4)

To a solution of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (5.00 g,12.8 mmol) in dioxane (128 mL) were added potassium carbonate (5.29 g,38.4 mmol), (R)-benzyl4-(2-hydroxy-3-mercaptopropyl)piperazine-1-carboxylate (3.97 g, 12.8mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (1.47 g, 2.56mmol) and tris(dibenzylideneacetone) dipalladium (1.20 g, 1.28 mmol).The mixture was stirred at 55° C. under nitrogen atmosphere for 8 hours.After completion, the mixture was diluted with tetrahydrofuran (300 mL)and filtered. The filtrate was concentrated and the residue was purifiedby silica gel column chromatography with a gradient ofdichloromethane/methanol=100/1 to 20/1 to afford (R)-benzyl4-(3-((7-chloro-4-hydroxy-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-8-yl)thio)-2-hydroxypropyl)piperazine-1-carboxylate(5.70 g, 78% yield) as a yellow solid. MS (ESI) m/z: 573.5 [M+H]⁺.

(S)-benzyl4-((10-chloro-7-hydroxy-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperazine-1-carboxylate(5)

To a mixture of (R)-benzyl4-(3-((7-chloro-4-hydroxy-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-8-yl)thio)-2-hydroxypropyl)piperazine-1-carboxylate(4.66 g, 8.1 mmol) and triphenylphosphine (4.26 g, 16.2 mmol) intetrahydrofuran (81 mL) was added diethyl azodicarboxylate (2.81 g, 16.2mmol) at 0° C. The mixture was stirred at 0° C. for 45 min. Aftercompletion, the mixture was poured into ice-water (300 mL) and extractedwith ethyl acetate (3×200 mL). After concentration, the residue waspurified by flash chromatography column (C18, acetonitrile/water=30% to95%) to afford (S)-benzyl4-((10-chloro-7-hydroxy-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperazine-1-carboxylate(3.14 g, 70% yield) as a white solid. MS (ESI) m/z: 555.5 [M+H]⁺.

(2R,5S)-tert-butyl4-((S)-3-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-10-chloro-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(6)

To a mixture of (S)-benzyl4-((10-chloro-7-hydroxy-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperazine-1-carboxylate(1.77 g, 3.19 mmol) and potassium carbonate (4.40 g, 3.19 mmol) inacetonitrile (106 mL) was added 4-methylbenzenesulfonic anhydride (2.08g, 6.38 mmol) at 25° C. The mixture was stirred at 25° C. for 3 hours.After completion, (2R,5S)-tert-butyl2,5-dimethylpiperazine-1-carboxylate (1.36 g, 6.38 mmol) was added intothe reaction solution. The reaction mixture was stirred at 25° C. for 1hour. After completion, the mixture was poured into ice-water (300 mL)and extracted with ethyl acetate (200 mL×3). After concentration, theresidue was purified by flash chromatography column (C18,acetonitrile/water=20% to 95%) to afford (2R,5S)-tert-butyl4-((S)-3-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-10-chloro-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(1.43 g, 60% yield) as a pale-white solid. MS (ESI) m/z: 751.1 [M+H]⁺.

(2R,5S)-tert-butyl4-((3S)-3-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(7)

To a solution of (2R,5S)-tert-butyl4-((S)-3-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-10-chloro-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(1 g, 1.3 mmol) in 1,4-dioxane (15 mL) and water (3 mL) were addedtripotassium phosphate (1.1 g, 5.2 mmol), (2,4-difluorophenyl)boronicacid (1.67 g, 10.6 mmol) and Chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(202 mg, 0.26 mmol). The mixture was stirred at 85° C. under nitrogenatmosphere for 4 hours. After completion, the mixture was diluted withtetrahydrofuran (300 mL) and filtered. The filtrate was concentrated andthe residue was purified by silica gel column chromatography with agradient of dichloromethane/methanol=100/1 to 30/1 to afford(2R,5S)-tert-butyl4-((3S)-3-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(1.00 g, 93% yield) as a yellow solid. MS (ESI) m/z: 829.5 [M+H]⁺.

(2R,5S)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-5-oxo-3-(piperazin-1-ylmethyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(8)

To a mixture of (2R,5S)-tert-butyl4-((3S)-3-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(1.00 g, 1.20 mmol) in ethanol (15 ml) was added Pd/C (0.300 g, 30%w/w). The mixture was stirred at room temperature under hydrogenatmosphere for 1 hour. After completion, the mixture was filtered andconcentrated. The residue was purified by silica gel columnchromatography eluting with dichloromethane/methanol (15/1) to afford(2R,5S)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-5-oxo-3-(piperazin-1-ylmethyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(600 mg, 71% yield) as a yellow solid. MS (ESI) m/z: 695.7 [M+H]⁺.

(2R,5S)-tert-butyl4-((3S)-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(9)

To a mixture of (2R,5S)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-5-oxo-3-(piperazin-1-ylmethyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(400 mg, 0.57 mmol) and sodium cyanoborohydride (359 mg, 5.70 mmol) intetrahydrofuran (5 mL) and methanol (5 mL) was added(1-ethoxycyclopropoxy)trimethylsilane (991 mg, 5.70 mmol) at 25° C.under nitrogen atmosphere. The reaction solution was heated to 85° C.for 12 hours. After completion, the mixture was filtered andconcentrated. the residue was purified by silica gel columnchromatography eluting with dichloromethane/methanol (30/1) to afford(2R,5S)-tert-butyl4-((3S)-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(300 mg, 71% yield) as a yellow solid. MS (ESI) m/z: 735.9 [M+H]⁺.

(3S)-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(10)

To a cooled mixture of (2R,5S)-tert-butyl4-((3S)-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(300 mg, 0.40 mmol) in dichloromethane (5 mL) was added trifluoroaceticacid (1 mL) at 0° C. The reaction solution was stirred at roomtemperature for 1 hour. After completion, the mixture was concentratedand the residue was purified by silica gel column chromatography elutingwith dichloromethane/methanol (15/1) to afford(3S)-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(200 mg, 78% yield) as a yellow solid. MS (ESI) m/z: 635.8 [M+H]⁺.

(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(11)

To a mixture of(3S)-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(180 mg, 0.28 mmol) and triethyl amine (56 mg, 0.56 mmol) indichloromethane (5 mL) was added acrylic anhydride (70 mg, 0.56 mmol) at0° C. The mixture was stirred at 0° C. for 1 hour. After completion, themixture was poured into ice-water (50 mL) and extracted with ethylacetate (3×20 mL). After concentration, the residue was purified bypreparative high performance liquid chromatography (20% to 95%acetonitrile in water) to afford(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(130 mg, 67% yield) as a white solid. MS (ESI) m/z: 689.8 [M+H]⁺.

The above racemate (130 mg) was dissolved with EtOH (10 mL) andseparated by chiral supercritical fluid chromatography (separationcondition: Column: Chiralpak AD-H, 5 μm 20×250 mm; Mobile Phase:CO₂:EtOH=60:40 at 25 mL/min; Temp: 25° C.; Wavelength: 254 nm) to affordtwo atropisomers of the title compounds (P1: 54.0 mg with 100% de andP2: 76.0 mg with 100% de); Chiral SFC Analytical condition: onCHIRALPAK® AD-H was using 5 μm 4.6×250 mm column, Mobile Phase:CO₂:EtOH=60:40 at 2.5 mL/min; Temp: 25° C.; Wavelength: 254 nm).

P1: ¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J=6.0, 1H), 7.31-7.27 (m, 1H),7.16-7.10 (m, 2H), 6.73-6.55 (m, 1H), 6.46-6.37 (m, 1H), 5.84-5.79 (m,1H), 5.44 (s, 1H), 5.13-4.70 (m, 1.5H), 4.47-4.36 (m, 1H), 4.11-3.70 (m,3H), 3.52-3.32 (m, 1.5H), 3.11-3.03 (m, 1H), 2.84-2.55 (m, 10H),1.52-1.43 (m, 7H), 0.57-0.42 (m, 4H); Chiral SFC fraction 1: e.e.=100%,Rt=4.96 min.

P2: ¹H NMR (400 MHz, CDCl₃) δ 7.87 (s, 1H), 7.28-7.19 (m, 1H), 7.09-6.98(m, 2H), 6.72-6.54 (m, 1H), 6.46-6.37 (m, 1H), 5.86-5.79 (m, 1H),5.42-5.35 (m, 1H), 5.12-4.68 (m, 1.5H), 4.52-4.33 (m, 1H), 4.19-3.67 (m,3H), 3.51-3.27 (m, 1.5H), 3.10-3.05 (m, 1H), 2.87-2.51 (m, 10H),1.52-1.29 (m, 7H), 0.59-0.44 (m, 4H); Chiral SFC fraction 2: e.e.=99.9%,Rt=5.50 min.

Example 417:7-(9-acryloyl-7,9-diazaspiro[bicyclo[3.3.1]nonane-3,3′-oxetan]-7-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

The title compound was prepared analogously to Example 84 where10-(2,4-difluorophenyl)-7-(7,9-diazaspiro[bicyclo[3.3.1]nonane-3,3′-oxetan]-7-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 10% yield as a white solid.

m/z (ESI, +ve)=605.2 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.48-7.43 (m, 1H), 7.32-7.25(m, 2H), 6.38-6.34 (m, 1H), 6.20-6.14 (m, 1H), 5.99-5.97 (m, 1H),4.55-4.43 (m, 2H), 4.33-4.27 (m, 3H), 4.12-4.04 (m, 3H), 3.65-3.52 (m,3H), 3.19-3.14 (m, 2H), 2.14-2.12 (m, 3H), 1.66-1.57 (m, 2H).

Step 1:(1R,5S)-Diethyl-9-benzyl-3-(phenylsulfonyl)-3,9-diazabicyclo[3.3.1]nonane-7,7-dicarboxylate

A solution of(1R,5S)-4-(benzenesulfonyl)-2,6-bis(chloromethyl)-1-(1-methylphenyl)piperazine(2 g, 4.8 mmol), 1,3-diethyl propanedioate (800 mg, 5 mmol),tetrabutylammonium bromide (160 mg, 0.5 mmol) and potassium carbonate(1.93 g, 14 mmol) in DMF (20 mL) was stirred at 100° C. for 16 hours.The solution was cooled to room temperature, diluted with water andextracted with ethyl acetate three times. The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure to obtain a residue that waspurified by silica gel chromatography (0-20% ethyl acetate in hexanes)to afford the title compound in 99% yield as colorless oil.

m/z (ESI, +ve)=501.2 (M+H)⁺.

Step 2:(1R,5S)-(9-benzyl-3-(phenylsulfonyl)-3,9-diazabicyclo[3.3.1]nonane-7,7-diyl)dimethanol

To a solution of (1R,5S)-diethyl9-benzyl-3-(phenylsulfonyl)-3,9-diazabicyclo[3.3.1]nonane-7,7-dicarboxylate(900 mg, 1.79 mmol) in THF (10 mL) was added lithium aluminum hydride(250 mg, 6.58 mmol) and the mixture was stirred at 0° C. for 2 hours.The reaction was quenched with 15% aqueous NaOH (1 mL), dried overmagnesium sulfate and filtered. The filtrate was concentrated underreduced pressure to afford the title compound (700 mg) as colorless oil.

m/z (ESI, +ve)=417.2 (M+H)⁺.

Step 3:(1R,5S)-9-benzyl-7-(phenylsulfonyl)-7,9-diazaspiro[bicyclo[3.3.1]nonane-3,3′-oxetane]

A solution of(1R,5S)-(9-benzyl-3-(phenylsulfonyl)-3,9-diazabicyclo[3.3.1]nonane-7,7-diyl)dimethanol(660 mg, 1.58 mmol), tosyl chloride (383 mg, 2.01 mmol) and triethylamine (0.8 mL, 5.74 mmol) in toluene (5 mL) was stirred at 100° C. for 2hours. The solution was cooled down to room temperature and concentratedunder reduced pressure to obtain a residue that was purified by reversephase chromatography to afford the title compound (410 mg) as colorlessoil.

m/z (ESI, +ve)=399.1 (M+H)⁺.

Step 4:(1R,5S)-7,9-dibenzyl-7,9-diazaspiro[bicyclo[3.3.1]nonane-3,3′-oxetane]

To a solution of9-benzyl-7-(phenylsulfonyl)-7,9-diazaspiro[bicyclo[3.3.1]nonane-3,3′-oxetane](1.36 g, 3.40 mmol) in THF (15 mL) at −78° C. was added KPPh₂ (0.5 Msolution in THF, 17 mL, 8.5 mmol) dropwise. The mixture was stirred at−78° C. for 3 hours. The reaction was quenched with 1M aqueous HCl (9mL) and the aqueous phase was separated and concentrated under reducedpressure. The residue was taken up in acetonitrile (15 mL) and potassiumcarbonate (1.4 g, 10.14 mmol) and benzyl bromide (822 mg, 5.10 mmol)were added. The resulting mixture was stirred at room temperature for 16hours. The solids were removed by filtration and the filtrate wasconcentrated and purified by reverse phase chromatography to afford thetitle compound (1.1 g) as colorless oil.

m/z (ESI, +ve)=349.2 (M+H)⁺.

Step 5: (1R,5S)-7,9-diazaspiro[bicyclo[3.3.1]nonane-3,3′-oxetane]

A mixture of(1R,5S)-7,9-dibenzyl-7,9-diazaspiro[bicyclo[3.3.1]nonane-3,3′-oxetane](1.1 g, 4.26 mol) and 10% palladium on activated carbon (2 g) inmethanol/ammonium hydroxide (10/1 mL) was stirred at 25° C. for 16 hunder hydrogen atmosphere. The mixture was filtered through celite andthe filtrate was concentrated to afford(1R,5S)-7,9-diazaspiro[bicyclo[3.3.1]nonane-3,3′-oxetane] (700 mg, 50%)as colorless oil.

m/z (ESI, +ve)=169.2 (M+H)⁺.

Step 6:10-(2,4-difluorophenyl)-7-(7,9-diazaspiro[bicyclo[3.3.1]nonane-3,3′-oxetan]-7-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

To a solution of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dione(100 mg, 0.25 mmol) and N,N-diisopropylethylamine (0.55 mL, 3.08 mmol)in toluene (1 mL), was added POCl₃ (1 mL) and the reaction mixture wasstirred at 120° C. for 1.5 hours. The solution was concentrated toobtain a residue that was dissolved in dichloroethane (1.5 mL) and asolution of (1R,5S)-7,9-diazaspiro[bicyclo[3.3.1]nonane-3,3′-oxetane](400 mg) and diisopropylethylamine (0.55 mL, 3.08 mL) in DMF (1.5 mL)was added at 0° C. under nitrogen atmosphere. The mixture was stirred at0° C. for 1 hours. The crude reaction mixture was purified by reversephase chromatography to afford the title compound (25 mg) as a yellowsolid.

m/z (ESI, +ve)=551.1 (M+H)⁺.

Example 418:10-(2,4-difluorophenyl)-7-(9-(2-fluoroacryloyl)-7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

To a solution of 2-fluoroacrylic acid (34 mg, 0.38 mmol) in DMF (3 mL)were added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium (160mg, 0.42 mmol) and N,N-diisopropylethylamine (99 mg, 0.76 mmol). After 5minutes,10-(2,4-difluorophenyl)-7-(7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(100 mg, 0.19 mmol) was added and stirring was continued at roomtemperature for two additional hours. The solvent was removed underreduced pressure to afford a residue that was purified by preparativeHPLC. The title compound was isolated n 12% yield as a light yellowsolid.

m/z (ESI, +ve)=595.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.50-7.45 (m, 1H), 7.40-7.34(m 1H), 7.30-7.25 (m, 1H), 5.47 (s, 1H), 5.48-5.27 (m, 1H), 5.29-5.18(m, 1H), 5.10-5.06 (m, 1H), 4.86-4.79 (m, 2H), 4.39-4.30 (m, 1H),4.20-3.96 (m, 3H), 3.123-3.13 (m, 4H), 2.98-2.89 (m, 2H).

Example 420:(E)-10-(2,4-difluorophenyl)-7-(9-(4-(dimethylamino)but-2-enoyl)-7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

To a solution of (E)-4-(dimethylamino)but-2-enoic acid (148 mg, 1.146mmol) in DMF (3 mL),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium (457 mg, 1.20mmol) and N,N-diisopropylethylamine (247 mg, 1.91 mmol) were added.After 5 minutes,10-(2,4-difluorophenyl)-7-(7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(100 mg, 0.19 mmol) was added over the reaction mixture and stirring wascontinued for another 2 hours. The solvent was removed under reducedpressure obtaining a residue that was purified by preparative HPLC toafford the title compound (2.7 mg, 2%) as a white solid.

m/z (ESI, +ve)=634.2 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.51-7.46 (m, 1H), 7.43-7.33(m, 1H), 7.32-7.24 (m, 1H), 6.75 (s, 1H), 5.15 (s, 1H), 4.92 (s, 1H),4.41-4.25 (m, 2H), 4.17-3.90 (m, 4H), 3.27-3.02 (m, 5H), 2.89-2.69 (m,4H), 2.46-2.37 (m, 3H), 2.18 (s, 3H).

Example 431:(3S)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-11-(2,4-difluorophenyl)-3-hydroxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

To a mixture of(3S)-11-(2,4-difluorophenyl)-3-hydroxy-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(50 mg, 0.09 mmol) and N,N-diisopropylethylamine (25 mg, 0.19 mmol) indichloromethane (2 mL), was added prop-2-enoyl prop-2-enoate (19 mg,0.15 mmol). The reaction mixture was stirred at room temperature for 1hour. The mixture was concentrated under reduced pressure affording aresidue that was purified by preparative HPLC. The title compound wasisolated in 4% yield as a white solid.

m/z (ESI, +ve)=567.2 (M+H)⁺.

¹H NMR (400 MHz, methanol-d4) δ 7.92 (s, 1H), 7.31-7.26 (m, 1H),7.12-7.06 (m, 2H), 6.87-6.75 (m, 1H), 6.29-6.25 (m, 1H), 5.81 (d, J=12.0Hz Hz, 1H), 4.41-4.33 (m, 2H), 4.18-4.11 (m, 1H), 4.04-3.99 (m, 1H),3.77-3.37 (m, 6H), 3.22-2.92 (m, 2H), 1.44-1.34 (m, 3H).

Step 1: (R)-3-(tritylthio)propane-1,2-diol

Potassium tert-butoxide (18.3 g, 0.18 mol) was added over a solution oftriphenylmethyl mercaptan (25 g, 0.091 mol) and(2R)-3-chloropropane-1,2-diol (10 g, 0.091 mol) in DMF (200 mL) at roomtemperature. The mixture was stirred for 16 hours and after that time itwas quenched with water. The resulting mixture was extracted with ethylacetate three times and the organic layers were combined and washed withbrine, dried over sodium sulfate and filtered. Evaporation of volatilesunder reduced pressure afforded a residue that was purified by columnchromatography on silica gel (0-50% ethyl acetate in hexanes). The titlecompound was isolated in 66% yield as yellow oil.

m/z (ESI, +ve)=373.1 (M+Na)⁺.

Step 2: (S)-1-((tert-butyldimethylsilyl)oxy)-3-(tritylthio)propan-2-ol

Imidazole (9.71 g, 0.14 mol) and tert-butyldimethylsilyl chloride (9.47g, 0.063 mol) were added over a solution of(2S)-3-[(triphenylmethyl)sulfanyl] propane-1,2-diol (20 g, 0.057 mol) inDMF (250 mL) at room temperature. After 16 hours, the reaction wasquenched by addition of water. The mixture was extracted with ethylacetate three times and the combined organic layers were washed withbrine, dried over sodium sulfate and filtered to afford a residue thatwas purified by silica gel chromatography (0-15% ethyl acetate inhexanes) to afford the title compound in 60% yield as a yellow oil.

m/z (ESI, +ve)=487.2 (M+Na)⁺.

Step 3:(S)-(2-(benzyloxy)-3-(tritylthio)propoxy)(tert-butyl)dimethylsilane

Sodium hydride (2.2 g, 0.090 mol) was added to a mixture oftert-butyl[(2S)-2-hydroxy-3-[(triphenylmethyl)sulfanyl] propoxy]dimethylsilane (28 g, 0.060 mol) in THF (200 mL) at 0° C. The mixturewas stirred at 0° C. for 30 minutes and benzyl bromide (11.3 g, 0.066mol) was added. The resulting solution was stirred at room temperaturefor 16 hours. The reaction was cooled down to 0° C. and quenched by theaddition of saturated aqueous ammonium chloride (100 mL) followed byextraction with ethyl acetate. The combined organic layers were washedwith brine, dried over sodium sulfate and filtered. Elimination ofvolatiles by reduced pressure and purification of the resulting residueby column chromatography on silica gel (0-10% ethyl acetate in hexanes)afforded the title compound in 71% yield as colorless oil.

m/z (ESI, +ve)=577.2 (M+Na)⁺.

Step 4: (S)-2-(benzyloxy)-3-mercaptopropan-1-ol

To a mixture of [(2S)-2-(benzyloxy)-3-[(triphenylmethyl) sulfanyl]propoxy] (tert-butyl) dimethylsilane (26.5 g, 0.0478 mol) indichloromethane/TFA (40 mL, 3:1 ratio) at 0° C., was addedtriethylsilane (16.7 g, 0.14 mol). The mixture was stirred at roomtemperature for 20 min and after that time the volatiles were removedunder reduced pressure at 40° C. The resulting residue was redissolvedwith saturated sodium bicarbonate and extracted three times with ethylacetate. The combined organic layers were washed with brine, dried oversodium sulfate and filtered. The crude solution was concentrated underreduced pressure and the resulting crude material purified by columnchromatography on silica gel (0-12% methanol in dichloromethane) toafford the title compound in 22% yield as colorless oil.

Step 5:8-(((S)-2-(benzyloxy)-3-hydroxypropyl)thio)-7-(2,4-difluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 where(S)-2-(benzyloxy)-3-mercaptopropan-1-ol was substituted in place of2-mercaptoethan-1-ol. The title compound was isolated in 53% yield as awhite solid.

m/z (ESI, +ve)=539.1 (M+H)⁺.

Step 6:(3S)-3-(benzyloxy)-11-(2,4-difluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where8-(((S)-2-(benzyloxy)-3-hydroxypropyl)thio)-7-(2,4-difluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.The title compound was isolated in 65% yield as a yellow solid.

m/z (ESI, +ve)=421.0 (M+H)⁺.

Step 7: tert-butyl(3S)-4-((3S)-3-(benzyloxy)-11-(2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3S)-3-(benzyloxy)-11-(2,4-difluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (S)-3-methylpiperazine-1-carboxylate were substituted inplace of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 73% yield as a yellow solid

m/z (ESI, +ve)=703.2 (M+H)⁺.

Step 8:(3S)-11-(2,4-difluorophenyl)-3-hydroxy-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

A 1M solution of boron tribromide in dichloromethane (1.1 mL) was addedover a solution of tert-butyl(3S)-4-((3S)-3-(benzyloxy)-11-(2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate(200 mg, 0.28 mmol) in dichloromethane (20 mL) precooled to −70° C. Thereaction mixture was stirred at −70° C. for 1 hour and quenched by theaddition of saturated sodium bicarbonate. The insoluble materials wereremoved by filtration and the filtrate was concentrated under reducedpressure to afford a residue that was purified by HPLC. The titlecompound was isolated in 61% yield as a yellow solid.

m/z (ESI, +ve)=513.1 (M+H)⁺.

Example 439:(E)-7-(9-(4,4-difluorobut-2-enoyl)-7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

To a solution of (E)-4,4-difluorobut-2-enoic acid (63 mg, 0.516 mmol) indichloromethane (3 mL), N,N,N′,N′-tetramethylchloroformamidiniumhexafluorophosphate (58 mg, 0.21 mmol) and N-methylimidazole (47 mg,0.57 mmol) were added. After 5 minutes,10-(2,4-difluorophenyl)-7-(7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(90 mg, 0.17 mmol) was added and the reaction mixture was stirred atroom temperature for 2 hours. The solvent was removed under reducedpressure to afford a residue that was purified by preparative HPLC. Thetitle compound was isolated in 4% yield as a white solid.

m/z (ESI, +ve)=627.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.50-7.46 (m, 1H), 7.38-7.35(m, 1H), 7.31-7.24 (m, 1H), 6.81-6.46 (m, 3H), 5.17 (s, 1H), 4.88 (s,1H), 4.37-4.33 (m, 1H), 4.31-4.21 (m, 1H), 4.18-3.94 (m, 3H), 3.32-3.10(m, 5H), 2.97-2.74 (m, 2H).

Example 440:(E)-10-(2,4-difluorophenyl)-7-(7-oxo-9-(4,4,4-trifluorobut-2-enoyl)-3,9-diazabicyclo[3.3.1]nonan-3-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

To a solution of (2E)-4,4,4-trifluorobut-2-enoic acid (43 mg, 0.31 mmol)in dichloromethane (1 mL) were added oxalyl chloride (59 mg, 0.45 mmol)and 2 drops of DMF. The reaction mixture was stirred at room temperaturefor 30 minutes and after that time a solution of10-(2,4-difluorophenyl)-7-(7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(80 mg, 0.15 mmol) and triethylamine (93 mg, 0.92 mmol) indichloromethane (1 mL) was added. The mixture stirred at roomtemperature for 1 hour. The solvent was removed under reduced pressureto afford a residue that was purified by preparative HPLC. The titlecompound was isolated in 4% yield as a white solid.

m/z (ESI, +ve)=645.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.59-7.43 (m, 2H), 7.37 (s,1H), 7.30-7.26 (m, 1H), 6.93-6.89 (m, 1H), 5.17 (m, 1H), 4.92 (m, 1H),4.33-4.17 (m, 2H), 4.17-3.97 (m, 3H), 3.30-3.14 (m, 5H), 3.09-2.96 (m,1H), 2.79-2.72 (m, 1H).

Example 442:(2S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(2,4-difluorophenyl)-2-((dimethylamino)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

Over a solution of(2S)-10-(2,4-difluorophenyl)-2-((dimethylamino)methyl)-7-((S)-2-methylpiperazin-1-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(38 mg) in acetonitrile (2 mL), triethylamine (0.11 mL) and acryloylchloride (0.014 mL) were added. The mixture was stirred at roomtemperature for 30 minutes and at that time quenched by the addition ofwater. The mixture was extracted with ethyl acetate, dried over sodiumsulfate and concentrated to afford a residue that was purified by HPLC.The title compound was isolated as a white solid in 49% yield

m/z (ESI, +ve)=594.2 (M+H)⁺.

Step 1: tert-Butyl(3S)-4-((3S)-11-(2,4-difluorophenyl)-3-hydroxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate

A solution of tert-butyl(3S)-4-((3S)-3-(benzyloxy)-11-(2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate(100 mg) in 2 mL of isopropanol was hydrogenated at atmospheric pressurein the presence of 75 mg of 10% palladium on activated carbon. After 12hours, the reaction was filtered through celite and the volatilesremoved under reduced pressure to afford a solid that was hydrogenatedfor a second time in 2 mL of isopropanol and 75 mg of 10% palladium onactivated carbon. The reaction was filtered through celite and thevolatiles removed under reduced pressure to afford the title compound asan orange solid.

m/z (ESI, +ve)=613.2 (M+H)⁺.

Step 2: tert-butyl(3S)-4-((3S)-11-(2,4-difluorophenyl)-3-((methylsulfonyl)oxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate

Over a solution of tert-Butyl(3S)-4-((3S)-11-(2,4-difluorophenyl)-3-hydroxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate(368 mg) in dichloromethane (6 mL) at room temperature,N,N-diisopropylethylamine (0.50 mL) and methanesulfonyl chloride (0.12mL) were added. The reaction was stirred for 3 hours, diluted withdichloromethane and washed with water. The organic layer was dried withsodium sulfate and concentrated under reduced pressure to afford anorange solid that was used in the next step without furtherpurification.

m/z (ESI, +ve)=691.2 (M+H)⁺.

Step 3: tert-Butyl(3S)-4-((2R)-10-(2,4-difluorophenyl)-2-((dimethylamino)methyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate

tert-Butyl(3S)-4-((3S)-11-(2,4-difluorophenyl)-3-((methylsulfonyl)oxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylateobtained in the previous step was taken up in 0.5 M solution ofN-methylamine in dioxane (2 mL) and heated at 100° C. in microwavereactor for two hours. The volatiles were removed under reduced pressureand the crude residue purified by chromatography in silica gel (0-10%methanol in ethyl acetate) to afford the title compound in 32% yield asa orange oil.

m/z (ESI, +ve)=640.2 (M+H)⁺.

Step 4:(2R)-10-(2,4-difluorophenyl)-2-((dimethylamino)methyl)-7-((S)-2-methylpiperazin-1-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

Over a solution of tert-butyl(3S)-4-((2R)-10-(2,4-difluorophenyl)-2-((dimethylamino)methyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(37 mg) in dichloromethane (1 mL), TFA (0.2 mL) was added. The mixturewas stirred at room temperature for 4 hours and at that time allvolatiles were removed under reduced pressure to afford a solid that wasused in the next step without further purification.

m/z (ESI, +ve)=539.2 (M+H)⁺.

Example 450:8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-11-(2,4-difluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where11-(2,4-difluorophenyl)-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-onein 51% yield as a yellow solid

m/z (ESI, +ve)=551.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J=4.0 Hz, 1H), 7.50-7.33 (m, 2H),7.26-7.23 (m, 1H), 6.91-6.75 (m, 1H), 6.21-6.15 (m, 1H), 5.74 (d, J=8Hz, 1H), 4.57-4.47 (m, 3H), 4.42-4.24 (m, 1H), 4.10-3.98 (m, 2H),3.62-3.48 (m, 1H), 3.46-2.92 (m, 4H), 2.11-1.86 (m, 2H), 1.33-1.28 (m,3H).

Step 1:7-(2,4-difluorophenyl)-8-((3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 where3-mercaptopropan-1-ol was substituted in place of 2-mercaptoethan-1-olin 56% yield as a white solid

m/z (ESI, +ve)=433.1 (M+H)⁺.

Step 2:11-(2,4-difluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(2,4-difluorophenyl)-8-((3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 52% yield as a white solid

m/z (ESI, +ve)=415.1 (M+H)⁺.

Step 3: tert-butyl(3S)-4-(11-(2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where11-(2,4-difluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (S)-3-methylpiperazine-1-carboxylate were substituted inplace of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 85% yield as a yellow solid.

m/z (ESI, +ve)=597.1 (M+H)⁺.

Step 4:11-(2,4-difluorophenyl)-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where(3S)-4-(11-(2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 92% yield as a yellow oil.

m/z (ESI, +ve)=497.1 (M+H)+.

Example 451:11-(2,4-difluorophenyl)-8-(9-(2-fluoroacryloyl)-7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

To a solution of 2-fluoroacrylic acid (34 mg, 0.38 mmol) in DMF (3 mL),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium (160 mg, 0.42mmol) and N,N-diisopropylethylamine (99 mg, 0.76 mmol) were added. After5 minutes,11-(2,4-difluorophenyl)-8-(7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(120 mg, 0.19 mmol) was added and the resulting solution stirred at roomtemperature for another 2 hours. The solvent was removed under reducedpressure to afford a residue that was purified by preparative HPLC. Thetitle compound was isolated in 15% as a light yellow solid.

m/z (ESI, +ve)=609.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ7.77 (s, 1H), 7.44-7.36 (m, 2H), 7.28-7.24(m, 1H), 5.47 (s, 1H), 5.38 (dd, J=24.0 Hz, 4.0 Hz, 1H), 5.06 (s, 1H),4.79 (s, 1H), 4.55-4.45 (m, 2H), 4.16-4.01 (m, 2H), 3.32-3.06 (m, 4H),3.00-2.73 (m, 2H), 2.55-2.52 (m, 2H), 2.14-1.89 (m, 2H).

Step 1:11-(2,4-difluorophenyl)-8-(7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 101, step 7 where11-(2,4-difluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dionewas substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dione.The title compound was isolated in 8% yield as a pale yellow solid.

m/z (ESI, +ve)=537.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.44-7.40 (m, 2H), 7.27-7.23(m, 1H), 4.50-4.44 (m, 2H), 3.87-3.83 (m, 2H), 3.65 (s, 2H), 3.27-3.13(m, 4H), 2.76-2.67 (m, 2H), 2.43-2.34 (m, 2H), 2.08-1.96 (m, 2H), 1.23(s, 1H).

Example 452:(E)-7-(9-(but-2-enoyl)-7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

To a solution of (E)-but-2-enoic acid (13 mg, 0.15 mmol) in acetonitrile(2 mL) were added N,N,N′,N′-tetramethylchloroformamidiniumhexafluorophosphate (38 mg, 0.14 mmol) and N-methylimidazole (33 mg,0.40 mmol). After 5 minutes,10-(2,4-difluorophenyl)-7-(7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(60 mg, 0.11 mmol) was added. The reaction mixture was stirred at roomtemperature for 2 hours. The solvent was removed under reduced pressureto afford a residue that was purified by preparative HPLC. The titlecompound was isolated in 5% yield as a white solid.

m/z (ESI, +ve)=591.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.48-7.47 (m, 1H), 7.38-7.37(m, 1H), 7.30-7.28 (m, 1H), 6.87-6.80 (m, 1H), 6.68-6.64 (m, 1H), 5.76(s, 1H), 5.15 (s, 1H), 4.95 (s, 1H), 4.32-4.24 (m, 2H), 4.16-3.97 (m,3H), 3.21-3.18 (m, 4H), 2.84-2.69 (m, 2H), 1.91-1.89 (m, 3H).

Example 453:7-(9-(but-2-ynoyl)-7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

The title compound was prepared analogously to Example 452, wherebut-2-ynoic acid was substituted in place of (E)-but-2-enoic acid. Thetitle compound was isolated in 18% yield as a white solid

m/z (ESI, +ve)=589.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.50-7.46 (m, 1H), 7.38-7.34(m, 1H), 7.30-7.26 (m, 1H), 5.05 (s, 2H), 4.31-4.30 (m, 1H), 4.13-4.04(m, 3H), 3.30-3.07 (m, 5H), 2.87-2.76 (m, 3H), 2.09-2.05 (m, 3H).

Example 454:(3S)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-11-(2,4-difluorophenyl)-3-(methyl(2,2,2-trifluoroethyl)amino)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

To a stirred solution of(3S)-11-(2,4-difluorophenyl)-3-(methyl(2,2,2-trifluoroethyl)amino)-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(8.5 mg, 0.01 mmol) at 0° C. in acetonitrile (2 mL),N,N-diisopropylethylamine (21 uL, 0.12 mmol) and prop-2-enoyl chloride(2.87 uL, 0.040 mmol) were added. The reaction was stirred for 5 minutesat 0° C., diluted with ethyl acetate and washed with water and brine.The organic layer was dried with sodium sulfate and concentrated toafford a yellow residue that was purified by silica (0-5% methanol indichloromethane) isolating the title compound as a light yellow solid in90% yield.

m/z (ESI, +ve)=662.2

¹H NMR (400 MHz, CDCl3) δ 7.75 (d, J=12.1 Hz, 1H), 7.15 (q, J=7.8 Hz,1H), 7.07-6.77 (m, 2H), 6.71-6.47 (m, 1H), 6.39 (dd, J=16.8, 1.9 Hz,1H), 5.79 (dd, J=10.4, 1.9 Hz, 1H), 5.10-4.58 (m, 2H), 4.58-4.08 (m,2H), 4.07-3.71 (m, 2H), 3.67-3.37 (m, 2H), 3.22-2.99 (m, 2H), 2.90 (t,J=8.5 Hz, 1H), 2.75 (dd, J=13.3, 7.7 Hz, 1H), 2.47 (d, J=3.9 Hz, 2H),1.60-1.35 (m, 3H), 1.35-1.10 (m, 3H).

Step 1: (R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol

To a vigorously stirred solution of triphenylmethanethiol (7.0 g, 25.33mmol) and (2R)-2-(benzyloxymethyl)oxirane (2.99 mL, 19.49 mmol) in THF(100 mL) at 0° C., sodium hydride (29 mmol) was added in three portionsover five minutes. The reaction was left in an ice bath to slowly warmto room temperature overnight. The reaction was diluted with ethylacetate (200 mL) and washed with water (×2) and brine. The organic layerwas collected, dried with sodium sulfate, and concentrated to afford atan oil. This oil was purified via column chromatography (5-50% ethylacetate in hexanes) isolating the title compound in 71% yield acolorless oil.

¹H NMR (400 MHz, CDCl3) δ 7.26-7.23 (m, 5H), 7.23-6.96 (m, 15H), 4.28(s, 2H), 3.35 (qd, J=6.6, 3.6 Hz, 1H), 3.23-3.05 (m, 2H), 2.31-2.15 (m,2H).

Step 2: (R)-1-(benzyloxy)-3-(tritylthio)propan-2-yl methanesulfonate

To a stirred solution of (R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol(3.5 g, 7.94 mmol) and triethylamine (23.8 mmol) in acetonitrile (100mL) cooled down to 0° C., methanesulfonyl chloride (2.13 mL) was added.The reaction was stirred at 0° C. for 30 minutes and let it warm up toambient temperature afterwards. After 2 hours, the reaction was dilutedwith ethyl acetate, washed with water and brine and the organic layerdried over sodium sulfate and concentrated to afford a brown oil. Thisoil was purified via column chromatography (5-40% ethyl acetate inhexanes) isolating the title compound in 91% yield as a thick colorlessoil.

¹H NMR (400 MHz, CDCl3) δ 7.45-7.42 (m, 5H), 7.34-7.24 (m, 15H),4.52-4.41 (m, 2H), 4.33 (qd, J=6.4, 4.8 Hz, 1H), 3.55-3.43 (m, 2H), 2.95(s, 3H), 2.64 (qd, J=13.4, 6.5 Hz, 2H).

Step 3:(S)-1-(benzyloxy)-N-methyl-N-(2,2,2-trifluoroethyl)-3-(tritylthio)propan-2-amine

To a stirred solution of (R)-1-(benzyloxy)-3-(tritylthio)propan-2-ylmethanesulfonate (1 g, 1.93 mmol) and DMA (6.4 mL) in a 20 mL microwavevial was added 2,2,2-trifluoro-N-methyl-ethanamine (5.45 mL, 38.56mmol). The vial was capped and heated at 50° C. for 13 hours. The crudereaction mixture was concentrated to afford light yellow oil. This crudeoil was purified via chromatography (5-45% ethyl acetate in hexanes)isolating the title compound in 24% yield as a colorless oil.

¹H NMR (400 MHz, CDCl3) δ 7.44 (dd, J=7.7, 1.8 Hz, 5H), 7.25-7.07 (m,15H), 4.40-4.28 (m, 2H), 3.31 (ddd, J=37.9, 9.5, 4.0 Hz, 2H), 2.71-2.49(m, 3H), 2.32-2.24 (m, 1H), 2.17-2.00 (m, 4H).

Step 4:(S)-3-(benzyloxy)-2-(methyl(2,2,2-trifluoroethyl)amino)propane-1-thiol

(S)-1-(benzyloxy)-N-methyl-N-(2,2,2-trifluoroethyl)-3-(tritylthio)propan-2-amine(150 mg, 0.28 mmol) was dissolved in a mixture of dichloromethane (1 mL)and TFA (1 mL) and treated with triethylsilane (1.12 g, 9.64 mmol) atambient temperature. The reaction was stirred for 2 hours. The crudereaction mixture was concentrated under reduced pressure to afford thetitle compound that was used in the next step without furtherpurification.

Step 5:8-(((S)-3-(benzyloxy)-2-(methyl(2,2,2-trifluoroethyl)amino)propyl)thio)-7-(2,4-difluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

A mixtureof(S)-3-(benzyloxy)-2-(methyl(2,2,2-trifluoroethyl)amino)propane-1-thiol(65.8 mg, 0.22 mmol), potassium carbonate (62. mg, 0.45 mmol), ethyleneglycol (0.1 mL), isopropanol (0.68 mL), and7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)-1H-quinazoline-2,4-dione(70 mg, 0.15 mmol) was degassed by bubbling nitrogen gas for 5 minutes.Copper iodide was then added (2.85 mg, 0.0100 mmol) and the mixturedegassed again for another 3 minutes. The reaction was heated at 85° C.overnight. The reaction was cooled to ambient temperature, diluted withethyl acetate, and washed with water and brine. The organic layer wasdried with sodium sulfate and concentrated to afford a crude oil thatwas purified by silica gel chromatography (0-10% methanol in ethylacetate) to afford the title compound in 95% yield as a white solid.

m/z (ESI, +ve)=634.2, RT: 5.25 min

Step 6:7-(2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-(methyl(2,2,2-trifluoroethyl)amino)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

A solution of8-(((S)-3-(benzyloxy)-2-(methyl(2,2,2-trifluoroethyl)amino)propyl)thio)-7-(2,4-difluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(90 .mg, 0.14 mmol) and 30 mg of 10% palladium on carbon in isopropanolwas hydrogenated for 18 hours. The reaction was filtered through celiteand concentrated to afford the title compound as a semisolid in 82%yield.

m/z (ESI, +ve)=544.1

Step 7:(3S)-11-(2,4-difluorophenyl)-3-(methyl(2,2,2-trifluoroethyl)amino)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

A solution of triphenylphosphine (76 mg, 0.29 mmol) and(4-chlorophenyl)methyl(NE)-N-[(4-chlorophenyl)methoxycarbonylimino]carbamate (106 mg, 0.29mmol) in 2 mL of THF was stirred at −10° C. for 10 minutes. To thismixture, a solution of7-(2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-(methyl(2,2,2-trifluoroethyl)amino)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(63 mg, 0.12 mmol) in 2 mL THF was added dropwise over 3 minutes. Thereaction was stirred for 1 hour at 0° C. An additional equivalent of(4-chlorophenyl)methyl(NE)-N-[(4-chlorophenyl)methoxycarbonylimino]carbamate andtriphenylphosphine in 0.5 mL of THF were added and the mixture stirredfor another 30 min. The reaction was diluted with ethyl acetate andwashed with water and brine. The organic layer was dried with sodiumsulfate and concentrated to a residue that was purified by columnchromatography (10-60% ethyl acetate in hexanes) to afford the titlecompound as a white solid in 82% yield.

m/z (ESI, +ve)=526.1

Step 8: tert-butyl(3S)-4-((3S)-11-(2,4-difluorophenyl)-3-(methyl(2,2,2-trifluoroethyl)amino)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(2,4-difluorophenyl)-3-(methyl(2,2,2-trifluoroethyl)amino)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (S)-3-methylpiperazine-1-carboxylate were substituted inplace of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 12% yield as a white solid

m/z (ESI, +ve)=708.3 (M+H)⁺.

Step 9:(3S)-11-(2,4-difluorophenyl)-3-(methyl(2,2,2-trifluoroethyl)amino)-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(3S)-4-((3S)-11-(2,4-difluorophenyl)-3-(methyl(2,2,2-trifluoroethyl)amino)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 99% yield as a colorless oil

Mass Spectrum (ESI) m/z=608.2 (M+H)+.

Example 464:(3S)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-11-(2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(2,4-difluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-onein 41% yield as a yellow solid

m/z (ESI, +ve)=581.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J=8.0 Hz, 1H), 7.50-7.33 (m, 2H),7.28-7.24 (m, 1H), 6.87-6.78 (m, 1H), 6.20-6.16 (m, 1H), 5.80-5.69 (m,1H), 4.67-4.44 (m, 4H), 4.26-4.24 (m, 1H), 4.17-4.13 (m, 1H), 4.01-3.97(m, 1H), 3.86-3.82 (m, 1H), 3.55-3. (m, 2H), 3.36-3.31 (m, 3H),3.24-3.07 (m, 1H), 3.01 (s, 1H), 1.26-1.20 (m, 3H).

Step 1: (S)-3-(tritylthio)propane-1,2-diol

Potassium tert-butoxide (18.3 g, 0.18 mol) was added over a solution oftriphenylmethyl mercaptan (25 g, 0.091 mol) and(2S)-3-chloropropane-1,2-diol (10 g, 0.091 mol) in DMF (200 mL) at 25°C. The mixture was stirred at room temperature for 16 hours and afterthat time it was quenched with water. The resulting mixture wasextracted with ethyl acetate three times and the organic layers werecombined and washed with brine, dried over sodium sulfate and filtered.Evaporation of volatiles under reduced pressure afforded a residue thatwas purified by column chromatography on silica gel (0-50% ethyl acetatein hexanes). The title compound was isolated in 66% yield as yellow oil.

m/z (ESI, +ve)=373.1 (M+Na)⁺.

Step 2: (S)-1-((tert-butyldimethylsilyl)oxy)-3-(tritylthio)propan-2-ol

Imidazole (9.71 g, 0.14 mol) and tert-butyldimethylsilyl chloride (9.47g, 0.063 mol) were added over a solution of(2S)-3-[(triphenylmethyl)sulfanyl] propane-1,2-diol (20 g, 0.057 mol) inDMF (250 mL) at room temperature. After 16 hours, the reaction wasquenched by the addition of water. The mixture was extracted with ethylacetate three times and the combined organic layers were washed withbrine, dried over sodium sulfate and filtered to afford a residue thatwas purified by silica gel chromatography (0-15% ethyl acetate inhexanes). The title compound was isolated in 60% yield as a yellow oil.

m/z (ESI, +ve)=487.2 (M+Na)⁺.

Step 3: (S)-tert-butyl(2-methoxy-3-(tritylthio)propoxy)dimethylsilane

To a solution oftert-butyl[(2S)-2-hydroxy-3-[(triphenylmethyl)sulfanyl]propoxy]dimethylsilane(21 g, 0.045 mol) in THF (200 mL) at 0° C., sodium hydride (1.62 g,0.068 mol) was added. After 30 minutes at 0° C., iodomethane (9.62 g,0.067 mol) was added and stirring was prolonged for another 3.5 hours.The reaction was quenched by addition of water and extracted with ethylacetate three times. The combined organic layers were washed with brine,dried over sodium sulfate and filtered to afford a residue that waspurified by silica gel chromatography. The tile compound was isolated in86% yield as a colorless oil.

m/z (ESI, +ve)=501.2 (M+Na)⁺.

Step 4: (S)-3-Mercapto-2-methoxypropan-1-ol

To a solution oftert-butyl[(2S)-2-methoxy-3-[(triphenylmethyl)sulfanyl]propoxy]dimethylsilane(18.7 g, 0.039 mol) in 180 mL of dichloromethane/TFA (3:1 ratio) at roomtemperature, was added triethylsilane (9.06 g, 0.078 mol). The mixturewas stirred at room temperature for 30 minutes. The reaction wasquenched by addition of water and extracted with dichloromethane threetimes. The combined organic layers were washed with brine, dried oversodium sulfate and filtered to afford a residue that was purified bysilica gel chromatography. The tile compound was isolated in 90% yieldas a colorless oil.

Step 5:7-(2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 where(S)-3-mercapto-2-methoxypropan-1-ol was substituted in place of2-mercaptoethan-1-ol in 73% yield as a yellow solid

m/z (ESI, +ve)=463.1 (M+H)⁺.

Step 4:(3S)-11-(2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 65% yield as a yellow solid

m/z (ESI, +ve)=445.1 (M+H)⁺.

Step 5: tert-butyl(3S)-4-((3S)-11-(2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (S)-3-methylpiperazine-1-carboxylate were substituted inplace of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 56% yield as a yellow solid

m/z (ESI, +ve)=627.1 (M+H)⁺.

Step 6:(3S)-11-(2,4-difluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(3S)-4-((3S)-11-(2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 95% yield as a yellow solid

m/z (ESI, +ve)=527.0 (M+H)⁺.

Example 465:(3R)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-11-(2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3R)-11-(2,4-difluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 10% yield as a yellow solid

m/z (ESI, +ve)=581.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J=4.0 Hz, 1H), 7.51-7.36 (m, 2H),7.28-7.24 (m, 1H), 6.89-6.76 (m, 1H), 6.20-6.15 (m, 1H), 5.76-5.70 (m,1H), 4.53-4.21 (m, 3H), 4.17-3.95 (m, 2H), 3.84 (s, 1H), 3.68-3.42 (m,3H), 3.35 (s, 3H), 3.21-3.07 (m, 2H), 3.01-2.91 (m, 1H), 1.32-1.27 (m,3H).

Step 1: (R)-3-(tritylthio)propane-1,2-diol

Potassium tert-butoxide (18.3 g, 0.18 mol) was added to a solution oftriphenylmethyl mercaptan (25 g, 0.091 mol) and(2R)-3-chloropropane-1,2-diol (10 g, 0.091 mol) in DMF (200 mL) at roomtemperature. The mixture was stirred for 16 hours and stopped by theaddition of water. The resulting mixture was extracted with ethylacetate three times and the organic layers were combined and washed withbrine, dried over sodium sulfate and filtered. Evaporation of volatilesunder reduced pressure afforded a residue that was purified by columnchromatography on silica gel (0-50% ethyl acetate in hexanes). The titlecompound was isolated in 510% yield as a yellow oil.

m/z (ESI, +ve)=373.1 (M+Na)⁺.

Step 2: (R)-1-((tert-butyldimethylsilyl)oxy)-3-(tritylthio)propan-2-ol

The titled compound was prepared analogously to example 464, step 2,where (2R)-3-[(triphenylmethyl)sulfanyl] propane-1,2-diol wassubstituted in place of (2S)-3-[(triphenylmethyl)sulfanyl]propane-1,2-diol. The title compound was isolated in 80% yield as ayellow oil.

m/z (ESI, +ve)=487.2 (M+Na)⁺.

Step 3: (R)-tert-butyl(2-methoxy-3-(tritylthio)propoxy)dimethylsilane

The titled compound was prepared analogously to example 464, step 3wheretert-butyl[(2R)-2-hydroxy-3-[(triphenylmethyl)sulfanyl]propoxy]dimethylsilanewas substituted in place oftert-butyl[(2S)-2-hydroxy-3-[(triphenylmethyl)sulfanyl]propoxy]dimethylsilane.The title compound was isolated in 90% yield as a colorless oil.

m/z (ESI, +ve)=501.2 (M+Na)⁺.

Step 4: (R)-3-Mercapto-2-methoxypropan-1-ol

The titled compound was prepared analogously to example 464, step 4,where (R)-tert-butyl(2-methoxy-3-(tritylthio)propoxy)dimethylsilane wassubstituted fortert-butyl[(2S)-2-methoxy-3-[(triphenylmethyl)sulfanyl]propoxy]dimethylsilane.The title compound was isolated in 85% as a colorless oil.

Step 5:7-(2,4-difluorophenyl)-8-(((R)-3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 where(R)-3-mercapto-2-methoxypropan-1-ol was substituted in place of2-mercaptoethan-1-ol. The title compound was isolated in 54% yield as ayellow oil.

m/z (ESI, +ve)=463.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 10.42 (d, J=18.4 Hz, 1H),8.28 (s, 1H), 7.49-7.33 (m, 2H), 7.25-7.19 (m, 1H), 4.84 (s, 1H),3.40-3.35 (m, 2H), 3.28 (d, J=10.8 Hz, 3H), 3.25-3.19 (m, 1H), 2.68-2.65(m, 1H), 2.35-2.31 (m, 1H).

Step 6:(3R)-11-(2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10,where7-(2,4-difluorophenyl)-8-(((R)-3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.The title compound was isolated in 56% yield as a white solid

m/z (ESI, +ve)=445.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 11.94 (d, J=4.0 Hz, 1H), 8.11 (d, J=7.2 Hz,1H), 7.47-7.24 (m, 3H), 4.39-4.17 (m, 2H), 3.87-3.78 (m, 1H), 3.67-3.58(m, 1H), 3.31 (d, J=8.8 Hz, 3H), 3.21-3.15 (m, 1H).

Step 7: tert-butyl(3S)-4-((3R)-11-(2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3R)-11-(2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (S)-3-methylpiperazine-1-carboxylate were substituted inplace of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 95% yield as a yellow solid

m/z (ESI, +ve)=627.2 (M+H)⁺.

Step 8:(3R)-11-(2,4-difluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(3S)-4-((3R)-11-(2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 95% yield as a yellow solid

m/z (ESI, +ve)=527.2 (M+H)⁺.

Example 486:8-(9-acryloyl-7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-11-(2,4-difluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where11-(2,4-difluorophenyl)-8-(7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 5% yield as a yellow solid

m/z (ESI, +ve)=591.2 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.88-7.78 (m, 1H), 7.47-7.39 (m, 2H),7.28-7.24 (m, 1H), 6.98-6.67 (m, 1H), 6.29-6.06 (m, 1H), 5.85-5.70 (m,1H), 5.16 (s, 1H), 4.93 (s, 1H), 4.75 (s, 1H), 4.54-4.49 (m, 2H),4.06-3.96 (m, 1H), 3.23-3.06 (m, 4H), 2.87-2.72 (m, 2H), 2.45-2.41 (m,2H), 2.06-1.97 (m, 2H).

Example 487:(3S)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 66% yield as a yellow solid.

m/z (ESI, +ve)=547.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.64 (d, J=12.0 Hz, 1H), 7.49-7.44 (m, 2H),7.30-7.25 (m, 1H), 6.86-6.77 (m, 1H), 6.21-6.15 (m, 1H), 5.76-5.73 (m,1H), 4.69-4.20 (m, 4H), 4.18-4.03 (m, 1H), 3.96 (s, 1H), 3.88-3.80 (m,1H), 3.64-3.38 (m, 3H), 3.35 (s, 3H), 3.11-2.97 (m, 2H), 1.31-1.24 (m,3H).

Step 1:6-chloro-7-(2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-methoxypropyl)thio)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 where(S)-3-mercapto-2-methoxypropan-1-ol was substituted in place of2-mercaptoethan-1-ol in 81% yield as a yellow solid

m/z (ESI, +ve)=429.1 (M+H)⁺.

Step 2:(3S)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where6-chloro-7-(2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-methoxypropyl)thio)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 74% yield as a yellow solid

m/z (ESI, +ve)=411.0 (M+H)⁺.

Step 3: tert-butyl(3S)-4-((3S)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3S)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (S)-3-methylpiperazine-1-carboxylate were substituted inplace of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 69% yield as a yellow solid

m/z (ESI, +ve)=593.2 (M+H)⁺.

Step 4:(3S)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(3S)-4-((3S)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 67% yield as a yellow solid

m/z (ESI, +ve)=493.1 (M+H)⁺.

Example 488:(3R)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3R)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 22% yield as a yellow solid.

m/z (ESI, +ve)=547.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J=16.0 Hz, 1H), 7.51-7.38 (m, 2H),7.29-7.24 (m, 1H), 6.91-6.75 (m, 1H), 6.18 (dd, J=16.0, 4.0 Hz, 1H),5.74 (dd, J=12.0, 4.0 Hz, 1H), 4.78-4.56 (m, 2H), 4.45-4.34 (m, 2H),4.29-4.07 (m, 1H), 4.03-3.79 (m, 3H), 3.71-3.49 (m, 2H), 3.46-3.35 (m,3H), 3.17-3.07 (m, 1H), 2.99-2.88 (m, 1H), 1.29-1.20 (m, 3H).

Step 1:6-chloro-7-(2,4-difluorophenyl)-8-(((R)-3-hydroxy-2-methoxypropyl)thio)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 where6-chloro-7-(2,4-difluorophenyl)-8-iodoquinazoline-2,4(1H,3H)-dione and(R)-3-mercapto-2-methoxypropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol in 49% yield as a yellow solid

m/z (ESI, +ve)=429.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 10.16 (d, J=12 Hz, 1H), 8.05(s, 1H), 7.48-7.34 (m, 2H), 7.29-7.23 (m, 1H), 4.79 (s, 1H), 3.25 (d,J=6.4 Hz, 3H), 3.22-3.14 (m, 1H), 2.84-2.77 (m, 1H), 2.73-2.64 (m, 1H),2.57-2.52 (m, 1H), 2.47-2.34 (m, 1H).

Step 2:(3R)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where6-chloro-7-(2,4-difluorophenyl)-8-(((R)-3-hydroxy-2-methoxypropyl)thio)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 90% yield as a white solid

m/z (ESI, +ve)=411.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 11.81 (d, J=4.8 Hz, 1H), 7.87 (d, J=8.8 Hz,1H), 7.52-7.32 (m, 2H), 7.28-7.19 (m, 1H), 4.35-2.25 (m, 1H), 3.86-3.79(m, 1H), 3.58 (d, J=13.8 Hz, 1H), 3.31 (d, J=10.0 Hz, 3H), 3.18-3.06 (m,2H).

Step 3: tert-butyl(3S)-4-((3R)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3R)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (S)-3-methylpiperazine-1-carboxylate were substituted inplace of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 88% yield as a yellow solid

m/z (ESI, +ve)=593.2 (M+H)⁺.

Step 4:(3R)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(3S)-4-((3R)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 81% yield as a yellow oil

m/z (ESI, +ve)=493.1 (M+H)⁺.

Example 489:(3S)-8-(4-acryloylpiperazin-1-yl)-11-(2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(2,4-difluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 6% yield as a yellow solid.

m/z (ESI, +ve)=567.1 (M+H)+.

¹H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.44-7.42 (m, 2H), 7.28-7.24(m, 1H), 6.85-6.78 (m, 1H), 6.17 (d, J=16.0 Hz 1H), 5.75-5.72 (m, 1H),4.50-4.47 (m, 1H), 3.79-3.73 (m, 8H), 3.45-3.43 (m, 1H), 3.35 (s, 3H),3.20-3.11 (m, 1H), 2.53-2.51 (m, 2H).

Step 1:(3S)-11-(2,4-difluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where(3S)-11-(2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dionewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 92% yield as a yellow oil

m/z (ESI, +ve)=513.1 (M+H)⁺.

Example 490:(3R)-8-(4-acryloylpiperazin-1-yl)-11-(2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3R)-11-(2,4-difluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 26% yield as a yellow solid

m/z (ESI, +ve)=567.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.48-7.37 (m, 2H), 7.26 (t,J=12.0 Hz, 1H), 6.82 (dd, J=20.0, 12.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0Hz, 1H), 5.74 (dd, J=12.0, 4.0 Hz, 1H), 4.50-4.46 (m, 1H), 3.95-3.62 (m,9H), 3.52-3.40 (m, 3H), 3.20-3.11 (m, 1H), 2.57-2.55 (m, 2H).

Step 1: tert-butyl4-((3R)-11-(2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3R)-11-(2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 97% yield as a yellow solid

m/z (ESI, +ve)=613.1 (M+H)⁺.

Step 2:(3R)-11-(2,4-difluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl4-((3R)-11-(2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 86% yield as a yellow oil.

m/z (ESI, +ve)=513.1 (M+H)⁺.

Example 503:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 32% yield as a yellow solid.

m/z (ESI, +ve)=595.2 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.47-7.39 (m, 2H), 7.2 (m,1H), 6.81 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (d, J=16.0 Hz, 1H), 5.74 (d,J=8.0 Hz, 1H), 4.59 (m, 2H), 4.49-4.47 (m, 1H), 4.06 (d, J=12 Hz, 2H),3.86 (s, 1H), 3.46 (s, 1H), 3.35 (s, 2H), 3.31-3.06 (m, 4H), 2.52 (s,1H), 1.51-1.25 (m, 6H).

Step 1: tert-butyl(2S,6R)-4-((3S)-11-(2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(2,4-difluorophenyl)-8-hydroxy-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-oneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 69% yield as a yellow solid

m/z (ESI, +ve)=541.1 (M+H)⁺.

Step 2:(3S)-11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2S,6R)-4-((3S)-11-(2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 32% yield as a yellow solid

Example 504:(3S)-8-(4-acryloylpiperazin-1-yl)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-8-(piperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 39% yield as a yellow solid

m/z (ESI, +ve)=532.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.48-7.44 (m, 2H), 7.29-7.25(m, 1H), 6.82 (dd, J=16.0, 8.0 Hz, 1H), 6.17 (d, J=16.0 Hz, 1H), 5.74(d, J=8.0 Hz, 1H), 4.49-4.40 (m, 1H), 3.90-3.64 (m, 8H), 3.44-3.40 (m,1H), 3.35 (s, 3H), 3.31-3.29 (m, 1H), 3.17-3.08 (m, 1H), 2.52 (m, 1H).

Step 1: tert-butyl4-((3S)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3S)-10-chloro-11-(2,4-difluorophenyl)-8-hydroxy-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-oneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 89% yield as a yellow solid

m/z (ESI, +ve)=579.1 (M+H)⁺.

Step 2:(3S)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-8-(piperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl4-((3S)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 89% yield as a yellow solid

m/z (ESI, +ve)=479.1 (M+H)⁺.

Example 505:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-10-chloro-11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 16% yield as a yellow solid.

m/z (ESI, +ve)=561.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.50-7.41 (m, 2H), 7.30-7.25(m, 1H), 6.84-6.77 (m, 1H), 6.21-6.16 (m, 1H), 5.75-5.72 (m, 1H), 4.56(s, 2H), 4.46-4.43 (m, 1H), 4.08-4.03 (m, 2H), 3.87-3.86 (m, 1H),3.46-3.43 (m, 2H), 3.35-3.28 (m, 3H), 3.17-3.10 (m, 1H), 2.52-2.51 (m,2H), 1.43-1.34 (m, 6H).

Step 1:(3S)-10-chloro-11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3S)-10-chloro-11-(2,4-difluorophenyl)-8-hydroxy-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-oneand (2S,6R)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 89% yield as a yellow solid

m/z (ESI, +ve)=507.1 (M+H)⁺.

Example 507:(2S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(2,4-difluorophenyl)-2-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

Over a solution of(2S)-10-(2,4-difluorophenyl)-2-(methoxymethyl)-7-((S)-2-methylpiperazin-1-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(32 mg) in acetonitrile (1 mL), triethylamine (0.11 mL) and acryloylchloride (0.014 mL) were added. The mixture was stirred at roomtemperature for 30 minutes and at that time quenched by the addition ofwater. The mixture was extracted with ethyl acetate, dried over sodiumsulfate and concentrated to afford a residue that was purified by HPLC.The title compound was isolated as a white solid in 32% yield

m/z (ESI, +ve)=581.2 (M+H)⁺.

Step 1: tert-butyl(3S)-4-((2S)-10-(2,4-difluorophenyl)-2-(((methylsulfonyl)oxy)methyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate

Over a solution of tert-butyl(3S)-4-((3S)-11-(2,4-difluorophenyl)-3-hydroxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate(391 mg) in 3 mL of dichloroethane at room temperature,N,N-diisopropylethylamine (1.0 mL) and methanesulfonyl chloride (0.34mL) were added and the mixture heated at 80° C. for three hours. Thereaction was cooled down to room temperature and diluted withdichloromethane and water. The organic layer was separated and theaqueous layer extracted with dichloromethane twice. Evaporation ofvolatiles under reduced pressure afforded a crude residue that waspurified by silica gel chromatography (0-3% methanol in ethyl acetate).The title compound was isolated in 43% yield.

m/z (ESI, +ve)=691.2 (M+H)⁺.

Step 2: tert-Butyl(3S)-4-((2S)-10-(2,4-difluorophenyl)-2-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate

tert-butyl(3S)-4-((2S)-10-(2,4-difluorophenyl)-2-(((methylsulfonyl)oxy)methyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(95 mg) was dissolved in methanol (2 mL) and heated at 70° C. for threehours. The methanol was removed under reduced pressure and the crudematerial purified by chromatography in silica gel to afford the titlecompound in 43% yield as an orange solid.

m/z (ESI, +ve)=627.2 (M+H)⁺.

Step 3:(2S)-10-(2,4-difluorophenyl)-2-(methoxymethyl)-7-((S)-2-methylpiperazin-1-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

Over a solution of tert-butyl(3S)-4-((2S)-10-(2,4-difluorophenyl)-2-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-methylpiperazine-1-carboxylate(37 mg) in dichloromethane (1 mL), TFA (0.2 mL) was added. The mixturewas stirred at room temperature for 4 hours and at that time allvolatiles were removed under reduced pressure to afford a solid that wasused in the next step without further purification.

m/z (ESI, +ve)=627.2 (M+H)⁺.

Example 524:(3R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3R)-11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 25% yield as a white solid

m/z (ESI, +ve)=595.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.52-7.39 (m, 2H), 7.30-7.23(m, 1H), 6.81 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 2.0 Hz, 1H),5.74 (dd, J=16.0, 2.0 Hz, 1H), 4.78-4.40 (m, 4H), 4.17-4.09 (m, 2H),3.86-3.81 (m, 1H), 3.57-3.35 (m, 4H), 3.29-3.09 (m, 3H), 1.52-1.26 (m,6H).

Step 1:(3R)-11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3R)-11-(2,4-difluorophenyl)-8-hydroxy-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-oneand (2S,6R)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 90% yield as a yellow solid

m/z (ESI, +ve)=541.1 (M+H)⁺.

Example 525:(3R)-8-(4-acryloylpiperazin-1-yl)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3R)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-8-(piperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 19% yield as a yellow solid

m/z (ESI, +ve)=533.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.50-7.43 (m, 2H), 7.30-7.25(m, 1H), 6.82 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 2.0 Hz, 1H),5.74 (dd, J=16.0, 2.0 Hz, 1H), 4.49-4.41 (m, 1H), 3.90-3.63 (m, 9H),3.46-3.35 (m, 2H), 3.32-3.26 (m, 3H), 3.17-3.08 (m, 1H).

Step 1: tert-butyl4-((3R)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3R)-10-chloro-11-(2,4-difluorophenyl)-8-hydroxy-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-oneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 72% yield as a yellow solid

m/z (ESI, +ve)=579.0 (M+H)⁺.

Step 2:(3R)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-8-(piperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl4-((3R)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 89% yield as a yellow solid

m/z (ESI, +ve)=479.1 (M+H)⁺.

Example 526:(3R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-chloro-11-(2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3R)-10-chloro-11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 24% yield as a yellow solid

m/z (ESI, +ve)=561.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.50-7.45 (m, 2H), 7.30-7.25(m, 1H), 6.80 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 2.0 Hz, 1H),5.74 (dd, J=16.0, 2.0 Hz, 1H), 4.68-4.39 (m, 4H), 4.14-3.97 (m, 2H),3.88-3.86 (m, 1H), 3.50-3.35 (m, 3H), 3.30-3.06 (m, 4H), 1.47-1.17 (m,6H).

Step 1:(3R)-10-chloro-11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3R)-10-chloro-11-(2,4-difluorophenyl)-8-hydroxy-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-oneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 61% yield as a yellow solid

m/z (ESI, +ve)=507.1 (M+H)⁺.

Example 527:(R)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(R)-11-(4-fluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 9% yield as a yellow solid

m/z (ESI, +ve)=563.2 (M+H)+.

¹H NMR (400 MHz, DMSO) δ 7.78 (s, 1H), 7.35-7.34 (m, 4H), 6.90-6.78 (m,1H), 6.18 (6.21-6.15, 1H), 5.76-5.73 (m, 1H), 4.64-4.60 (m, 1H),4.53-4.49 (m, 1H), 4.42-4.38 (m, 1H), 4.30-4.25 (m, 1H), 4.12-3.99 (m,2H), 3.81-3.80 (m, 1H), 3.56-3.54 (m, 2H), 3.33 (s, 3H), 3.13-2.97 (m,3H), 1.30 (s, 3H).

Step 1: Methyl 3-amino-4′-fluoro-[1,1′-biphenyl]-4-carboxylate

The title compound was synthesized analogously to example 100, step 1where 4-fluorophenylboronic acid was substituted in place of(2,4-difluorophenyl)boronic acid. The title compound was isolated in 99%yield as a brown solid

m/z (ESI, +ve)=246.1 (M+H)⁺.

Step 2: Methyl 5-amino-4′-fluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate

The title compound was synthesized analogously to example 100, step 2where Methyl 3-amino-4′-fluoro-[1,1′-biphenyl]-4-carboxylate wassubstituted in place of methyl3-amino-2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylate. The title compoundwas isolated in 90% yield as a brown solid

m/z (ESI, +ve)=372.0 (M+H)⁺.

Step 3: Methyl5-acetamido-4′-fluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate

The title compound was synthesized analogously to example 100, step 3where methyl 5-amino-4′-fluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate wassubstituted in place of 2-amino-4-(2,4-difluorophenyl)-5-iodobenzoate.The title compound was isolated in 98% yield as a brown solid

m/z (ESI, +ve)=414.0 (M+H)⁺.

Step 4: Methyl5-acetamido-4′-fluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate

The title compound was synthesized analogously to example 100, step 4where methyl 5-acetamido-4′-fluoro-2-iodo-[1,1′-biphenyl]-4-carboxylatewas substituted in place of methyl4-(2,4-difluorophenyl)-2-acetamido-5-iodobenzoate. The title compoundwas isolated in 62% yield as a brown solid

m/z (ESI, +ve)=356.1 (M+H)⁺.

Step 5: Methyl5-amino-4′-fluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate

The title compound was synthesized analogously to example 100, step 5where methyl5-acetamido-4′-fluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylatewas substituted in place of methyl5-acetamido-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate.The title compound was isolated in 87% yield as a white solid

m/z (ESI, +ve)=314.1 (M+H)⁺.

Step 6: Methyl3-amino-4′-fluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate

The title compound was synthesized analogously to example 100, step 6where methyl5-amino-4′-fluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate wassubstituted in place of methyl5-amino-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate.The title compound was isolated in 74% yield as a white solid

m/z (ESI, +ve)=440.0 (M+H)⁺.

Step 7:3-Amino-4′-fluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylicacid

The title compound was synthesized analogously to example 100, step 7where methyl3-amino-4′-fluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylatewas substituted in place of methyl3-amino-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate.The title compound was isolated in 94% yield as a white solid

¹H NMR (400 MHz, DMSO-d6) δ8.18 (s, 1H), 7.29 (t, 2H), 7.16 (m, 2H).

Step 8:7-(4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 8where3-Amino-4′-fluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylicacid was substituted in place of3-amino-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylicacid. The title compound was isolated in 70% yield as a white solid.

m/z (ESI, +ve)=451.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.75 (s, 1H), 8.23 (s, 1H),7.41-7.31 (m, 2H), 7.21-7.11 (m, 2H).

Step 9:(R)-7-(4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (R)-3-mercapto-2-methoxypropan-1-ol was substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 58% yieldas a white solid.

m/z (ESI, +ve)=445.1 (M+H)⁺.

Step 10:(R)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(R)-7-(4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 53% yield as a yellow solid

m/z (ESI, +ve)=427.0 (M+H)⁺.

Step 11: tert-butyl(S)-4-((R)-11-(4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(R)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (S)-3-methylpiperazine-1-carboxylate were substituted inplace of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 76% yield as a yellow solid

m/z (ESI, +ve)=609.2 (M+H)⁺.

Step 12:(R)-11-(4-fluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(S)-4-((R)-11-(4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 84% yield as a yellow solid

m/z (ESI, +ve)=509.1 (M+H)⁺.

Example 528:(R)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-chloro-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(R)-10-chloro-11-(4-fluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 9% yield as a yellow solid

m/z (ESI, +ve)=529.2 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.42-7.28 (m, 4H), 6.91-6.76(m, 1H), 6.18 (dd, J=16.0 Hz, 8.0 Hz, 1H), 5.74 (d, J=8.0 Hz, 1H),4.73-4.58 (m, 1H), 4.49-4.34 (m, 2H), 4.29-4.20 (m, 0.5H), 4.16-4.07 (m,0.5H), 4.06-3.89 (m, 2H), 3.88-3.80 (m, 1H), 3.68-3.47 (m, 2H), 3.33 (s,4H), 3.19-3.13 (m, 0.5H), 3.13-3.03 (m, 1H), 3.00-2.89 (m, 0.5H),1.27-1.23 (m, 3H).

Step 1: Methyl 5-amino-2-chloro-4′-fluoro-[1,1′-biphenyl]-4-carboxylate

The title compound was prepared analogously to Example 84, step 15 where4-fluorophenylboronic acid was substituted in place of(2,4-difluorophenyl)boronic acid. The title compound was isolated in 57%yield as a yellow solid

m/z (ESI, +ve)=280.1 (M+H)⁺.

Step 2: Methyl3-amino-6-chloro-4′-fluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate

The title compound was prepared analogously to Example 84, step 16 whereMethyl 5-amino-2-chloro-4′-fluoro-[1,1′-biphenyl]-4-carboxylate wassubstituted in place of methyl5-amino-2-chloro-2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylate. The titlecompound was isolated in 85% yield as a white solid

m/z (ESI, +ve)=405.9 (M+H)⁺.

Step 3: 3-Amino-6-chloro-4′-fluoro-2-iodo-[1,1′-biphenyl]-4-carboxylicacid

The title compound was prepared analogously to Example 84, step 17 wheremethyl 3-amino-6-chloro-4′-fluoro-2-iodo-[1,1′-biphenyl]-4-carboxylatewas substituted in place of methyl3-amino-6-chloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate.The title compound was isolated in 95% yield as a yellow solid

m/z (ESI, +ve)=391.9 (M+H)⁺.

Step 4: 6-Chloro-7-(4-fluorophenyl)-8-iodoquinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 84, step 18 where3-amino-6-chloro-4′-fluoro-2-iodo-[1,1′-biphenyl]-4-carboxylic acid wassubstituted in place of3-amino-6-chloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylicacid. The title compound was isolated in 60% yield as a yellow solid

m/z (ESI, +ve)=416.9 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ=11.76 (s, 1H), 9.47 (s, 1H), 8.00 (s, 1H),7.45-7.31 (m, 2H), 7.29-7.16 (m, 2H).

Step 5:(R)-6-chloro-7-(4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 where6-Chloro-7-(4-fluorophenyl)-8-iodoquinazoline-2,4(1H,3H)-dione and(R)-3-mercapto-2-methoxypropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 60% yieldas a white solid

m/z (ESI, +ve)=411 (M+H)⁺.

Step 6:(R)-10-chloro-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(R)-6-chloro-7-(4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)quinazoline-2,4(1H,3H)-dione

was substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 90% yield as a yellow solid

m/z (ESI, +ve)=393.0 (M+H)⁺.

Step 7: tert-butyl(S)-4-((R)-10-chloro-11-(4-fluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(R)-10-chloro-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (S)-3-methylpiperazine-1-carboxylate were substituted inplace of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 90% yield as a yellow solid

m/z (ESI, +ve)=575.2 (M+H)⁺.

Step 8:(R)-10-chloro-11-(4-fluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(S)-4-((R)-10-chloro-11-(4-fluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 67% yield as a yellow solid

m/z (ESI, +ve)=475.1 (M+H)⁺.

Example 529:(3S)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 14% yield as a yellow solid

m/z (ESI, +ve)=580.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ7.84-7.77 (m, 2H), 7.68-7.64 (m, 1H),6.93-6.74 (m, 1H), 6.20-6.16 (m, 1H), 5.76-5.72 (m, 1H), 4.62-4.40 (m,3H), 4.30-4.02 (m, 2H), 4.02-3.82 (m, 2H), 3.65-3.40 (m, 2H), 3.38-3.33(m, 4H), 3.24-2.91 (m, 2H), 1.31-1.24 (m, 3H).

Step 1: Methyl2-amino-5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

To a mixture of methyl 2-amino-4-bromo-5-chlorobenzoate (40 g, 0.1512mol) in dioxane (200 mL), bis(pinacolato)diboron (57.6 g, 0.2268 mol),Pd(dppf)Cl₂ (5.52 g, 0.0076 mol) and potassium acetate (44.12 g, 0.4536mol) were added. The mixture was stirred at 100° C. for 16 hours and thesolids removed by filtration. Evaporation of volatiles under reducedpressure afforded a residue that was purified by silica gelchromatography. The title compound was isolated in 74% yield as a yellowsolid.

m/z (ESI, +ve)=312.1 (M+H)⁺.

Step 2: Methyl5-amino-2,5′-dichloro-2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylate

To a mixture of methyl2-amino-5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(25.5 g, 0.0818 mol) in 300 mL of dioxane/water (5:1 ratio) was added1-bromo-5-chloro-2,4-difluorobenzene (15.5 g, 0.0682 mol), cesiumcarbonate (66.66 g, 0.2046 mol) and Pd(dppf)Cl₂ (2.5 g, 0.0034 mol). Theresulting mixture was stirred at 100° C. for 1.5 hours and after thattime the solids were removed by filtration. The reaction mixture wasdiluted with water and extracted with ethyl acetate three times. Thecombined organic layers were washed with brine, dried over sodiumsulfate and concentrated under reduced pressure to afford a residue thatwas purified by silica gel chromatography. A second purification bychromatography on C18 column using acetonitrile in water (0-100%) asmobile phase afforded the title compound in 90% yield as a yellow oil.

m/z (ESI, +ve)=332.0 (M+H)⁺.

Step 3: Methyl3-amino-5′,6-dichloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate

The title compound was prepared analogously to Example 84, step 16 wheremethyl5-amino-2,5′-dichloro-2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylate wassubstituted in place of methyl5-amino-2-chloro-2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylate. The titlecompound was isolated in 80% yield as a white solid.

m/z (ESI, +ve)=457.9 (M+H)⁺.

Step 4:3-Amino-5′,6-dichloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylicacid

The title compound was prepared analogously to Example 84, step 17 whereMethyl3-amino-5′,6-dichloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylatewas substituted in place of methyl3-amino-6-chloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate.The title compound was isolated in 95% yield as a yellow solid

m/z (ESI, +ve)=443.9 (M+H)⁺.

Step 5:6-chloro-7-(5-chloro-2,4-difluorophenyl)-8-iodoquinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 84, step 18 where3-Amino-5′,6-dichloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylicacid was substituted in place of3-amino-6-chloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylicacid. The title compound was isolated in 86% yield as a yellow solid

m/z (ESI, +ve)=468.9 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ=11.79 (s, 1H), 11.17 (s, 1H), 8.05 (s, 1H),7.8 (t, J=8.0 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H).

Step 6:6-chloro-7-(5-chloro-2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-methoxypropyl)thio)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 where6-chloro-7-(5-chloro-2,4-difluorophenyl)-8-iodoquinazoline-2,4(1H,3H)-dioneand (S)-3-mercapto-2-methoxypropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol in 61% yield as a yellow solid

m/z (ESI, +ve)=463.0 (M+H)⁺.

Step 7:(3S)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where6-chloro-7-(5-chloro-2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-methoxypropyl)thio)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 60% yield as a yellow solid

m/z (ESI, +ve)=445.0 (M+H)⁺.

Step 8: tert-butyl(3S)-4-((3S)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3S)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (S)-3-methylpiperazine-1-carboxylate were substituted inplace of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 73% yield as a yellow solid

m/z (ESI, +ve)=627.1 (M+H)⁺.

Step 9:(3S)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(3S)-4-((3S)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 74% yield as a yellow solid

m/z (ESI, +ve)=527.0 (M+H)⁺.

Example 530:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 37% yield as a yellow solid

m/z (ESI, +ve)=595.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.93-7.67 (m, 3H), 6.80 (dd, J=16.0 Hz, 8.0Hz, 1H), 6.19 (d, J=16.0 Hz, 1H), 5.74 (d, J=8.0 Hz, 1H), 4.56 (s, 2H),4.48-4.44 (m, 2H), 4.09-4.00 (m, 2H), 3.88 (s, 1H), 3.54-3.37 (m, 1H),3.35 (s, 3H), 3.28 (s, 2H), 3.18-3.16 (d, J=12.0 Hz, 1H), 1.50-1.24 (m,6H).

Step 1:(3S)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3S)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2S,6R)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 61% yield as a yellow solid

m/z (ESI, +ve)=541.0 (M+H)⁺.

Example 532:(S)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-11-(4-fluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 30% yield as a white solid

m/z (ESI, +ve)=563.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.34 (d, J=8.0 Hz, 4H),6.92-6.76 (m, 1H), 6.18 (dd, J=16.0, 8.0 Hz, 1H), 5.74 (dd, J=12.0, 4.0Hz, 1H), 4.70-4.39 (m, 3H), 4.28-4.24 (m, 1H), 4.16-3.97 (m, 2H),3.83-3.79 (m, 1H), 3.56-3.51 (m, 2H), 3.34 (s, 3H), 3.13-2.98 (m, 3H),1.33-1.29 (m, 3H).

Step 1:(S)-7-(4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 where7-(4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-3-mercapto-2-methoxypropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 50% yieldas a yellow solid

m/z (ESI, +ve)=445.0 (M+H)⁺.

Step 2:(S)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(S)-7-(4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 66% yield as a yellow solid

m/z (ESI, +ve)=427.1 (M+H)⁺.

Step 3: tert-butyl(S)-4-((S)-11-(4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(S)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (S)-3-methylpiperazine-1-carboxylate were substituted inplace of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 59% yield as a yellow solid

m/z (ESI, +ve)=609.2 (M+H)⁺.

Step 4:(S)-11-(4-fluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(S)-4-((S)-11-(4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 86% yield as a yellow solid

m/z (ESI, +ve)=509.1 (M+H)⁺.

Example 533:(3R)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3R)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 34% yield as a yellow solid

m/z (ESI, +ve)=615.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ=7.83-7.66 (m, 3H), 6.91-6.74 (m, 1H), 6.19(dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0, 4.0 Hz, 1H), 4.80-4.31 (m,4H), 4.17 (m, 3H), 3.85 (s, 1H), 3.54 (s, 2H), 3.37-3.32 (m, 3H),3.22-3.18 (m, 2H), 1.33-1.28 (m, 3H).

Step 1: methyl3-amino-5′-chloro-2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylate

A mixture of methyl 2-amino-4-bromobenzoate (30 g, 0.130 mol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (50 g, 0.197mol), Pd(dppf)Cl₂ (9.5 g, 13 mmol) and KOAc (38 g, 0.388 mol) in1,4-dioxane (400 mL) was stirred at 100° C. for 16 hours. After thattime, the mixture was filtered and the filtrate was concentrated underreduced pressure to afford a residue that was purified by silica gelcolumn with ethyl acetate in hexanes (0-10%). The title compound wasisolated in quantitative yield as a white solid.

m/z (ESI, +ve)=278.2 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ=7.68 (d, J=8.0 Hz, 1H), 7.18 (s, 1H), 6.79(d, J=8.0 Hz, 1H), 6.63 (s, 2H), 3.79 (s, 3H), 1.29 (s, 12H).

Step 2: methyl3-amino-5′-chloro-2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylate

A mixture of methyl2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (36 g,0.121 mol), 1-bromo-5-chloro-2,4-difluorobenzene (27 g, 0.119 mol),Pd(dppf)Cl₂ (17 g, 23.3 mmol) and Cs₂CO₃ (116 g, 0.356 mol) in1,4-dioxane-water (300:60 mL) was stirred at 100° C. for 2 hours. Thesolution was cooled down to room temperature and filtered. The filtratewas concentrated under reduced pressure to afford a residue that waspurified by silica gel chromatography with ethyl acetate in hexanes(0-8%). The title compound was isolated as a white solid in 83% yield.

m/z (ESI, +ve)=298.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ=7.79-7.74 (m, 2H), 7.70-7.65 (m, 1H), 6.96(s, 1H), 6.77 (s, 2H), 6.71-6.68 (m, 1H), 3.81 (s, 3H).

Step 3: methyl5-amino-5′-chloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate

N-Iodosuccinamide (30 g, 0.133 mol) was added to a solution of methyl3-amino-5′-chloro-2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylate (38 g,0.128 mol) in DMF (200 mL) at room temperature. The mixture was stirredfor 36 hours and after that time ethyl acetate (1 L) was added. Theorganic mixture was washed with sequentially washed with aqueousNa₂S₂O₃, water and brine. The organic layer was dried over sodiumsulfate and filtered to afford a residue that was purified by silica gelchromatography (ethyl acetate in hexanes). The title compound wasisolated in 87% yield as a yellow solid.

m/z (ESI, +ve)=423.9 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ=8.15 (s, 1H), 7.68-7.61 (m, 2H), 6.87 (s,2H), 6.81 (s, 1H), 3.83 (s, 3H).

Step 4: methyl5-acetamido-5′-chloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate

To a solution of methyl5-amino-5′-chloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate(47 g, 0.111 mol) in AcOH (200 mL), acetic anhydride (14.5 g, 0.144 mol)was added and the resulting mixture was stirred at 100° C. for 2 hours.The reaction was cooled to room temperature and quenched by the additionof water (200 mL) inducing the precipitation of the desired finalproduct. This solid was filtered and dried under reduced pressure toafford the title compound in 99% yield as an off-white solid.

m/z (ESI, +ve)=465.9 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ=10.52 (s, 1H), 8.36 (s, 1H), 8.18 (s, 1H),7.75-7.66 (m, 2H), 3.83 (s, 3H), 2.12 (s, 3H).

Step 5: methyl5-acetamido-5′-chloro-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate

To a solution of methyl5-acetamido-5′-chloro-2′,4′-difluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate(10 g, 21.5 mmol), CuI (5.7 g, 30.0 mmol) and TBAI (4 g, 10.8 mmol) inHMPA (50 mL) at 90° C., was added methyl2,2-difluoro-2-(fluorosulfonyl)acetate (41.2 g, 214.6 mmol). The mixturewas stirred at 90° C. for 16 hours and after being cooled down to roomtemperature, water was added followed by filtration of the solids. Theaqueous filtrate was extracted with ethyl acetate three times and thecombined organic layers washed with water, brine and dried over sodiumsulfate. Filtration and evaporation of volatiles under reduced pressureafforded a residue that was purified by silica gel chromatography (0-15%ethyl acetate in hexanes). The tile compound was isolated in 82% yieldas a yellow solid.

m/z (ESI, +ve)=408.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ=10.81 (s, 1H), 8.34 (s, 1H), 8.26 (s, 1H),7.78-7.61 (m, 2H), 3.93 (s, 3H), 2.18 (s, 3H).

Step 6: methyl5-amino-5′-chloro-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate

The title compound was synthesized analogously to example 100, step 5where methyl5-acetamido-5′-chloro-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylatewas substituted in place of methyl5-acetamido-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate.The title compound was isolated in 92% yield as a white solid

m/z (ESI, +ve)=366.0 (M+H)⁺.

Step 7: methyl3-amino-5′-chloro-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate

The title compound was synthesized analogously to example 100, step 6where methyl5-amino-5′-chloro-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylatewas substituted in place of methyl5-amino-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate.The title compound was isolated in 86% yield as a white solid

m/z (ESI, +ve)=491.9 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ=8.19 (s, 1H), 7.76-7.73 (m, 1H), 7.67-7.63(m, 1H), 7.48-7.44 (m, 2H), 3.90 (s, 3H).

Step 8:3-amino-5′-chloro-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylicacid

The title compound was synthesized analogously to example 100, step 7where methyl3-amino-5′-chloro-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylatewas substituted in place of methyl3-amino-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate.The title compound was isolated in 99% yield as a white solid

m/z (ESI, +ve)=477.8 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ=13.60 (s, 1H), 8.19 (s, 1H), 7.77-7.72 (m,1H), 7.67-7.63 (m, 1H), 7.57-7.48 (m, 2H).

Step 9:7-(5-chloro-2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 8where3-Amino-4′-fluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylicacid was substituted in place of3-amino-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylicacid. The title compound was isolated in 57% yield as a white solid.

m/z (ESI, +ve)=502.9 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ=11.93 (s, 1H), 9.99 (s, 1H), 8.27 (s, 1H),7.83-7.78 (m, 1H), 7.72-7.68 (m, 1H).

Step 11:7-(5-chloro-2,4-difluorophenyl)-8-(((R)-3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(5-chloro-2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (R)-3-mercapto-2-methoxypropan-1-ol was substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 70% yieldas a white solid.

m/z (ESI, +ve)=497.0 (M+H)⁺.

Step 12:(3R)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(5-chloro-2,4-difluorophenyl)-8-(((R)-3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 55% yield as a yellow solid

Step 13: tert-butyl(3S)-4-((3R)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3R)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (S)-3-methylpiperazine-1-carboxylate were substituted inplace of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 61% yield as a yellow solid

m/z (ESI, +ve)=661.0 (M+H)⁺.

Step 14:(3R)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(3S)-4-((3R)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated as a yellow oil

m/z (ESI, +ve)=561.0 (M+H)⁺.

Example 534:(3R)-8-(4-acryloylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3R)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 27% yield as a yellow solid

m/z (ESI, +ve)=601.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ=7.90 (s, 1H), 7.80-7.76 (m, 2H), 6.82 (dd,J=16.0, 8.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.51-4.47 (m, 1H), 3.84-3.80 (m, 9H), 3.47-3.43 (m, 1H),3.40-3.35 (m, 3H), 3.22-3.18 (m, 2H).

Step 1: tert-butyl4-((3R)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21(3R)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 68% yield as a yellow solid

m/z (ESI, +ve)=647.1 (M+H)⁺.

Step 2:(3R)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl4-((3R)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 70% yield as a yellow solid

m/z (ESI, +ve)=547.0 (M+H)⁺.

Example 535:(3R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3R)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 32% yield as a yellow solid

m/z (ESI, +ve)=629.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ=8.04 (s, 1H), 7.87-7.69 (m, 2H), 6.81 (dd,J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.67-4.46 (m, 3H), 4.08-4.04 (m, 2H), 3.88-3.84 (m, 1H),3.49-3.44 (m, 1H), 3.35 (s, 3H), 3.32-3.21 (m, 3H), 3.17 (s, 1H),1.53-1.27 (m, 6H).

Step 1:(3R)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3R)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 63% yield as a yellow solid

m/z (ESI, +ve)=575.0 (M+H)⁺.

Example 536:(S)-8-(4-acryloylpiperazin-1-yl)-10-chloro-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-10-chloro-11-(4-fluorophenyl)-3-methoxy-8-(piperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 27% yield as a yellow solid

m/z (ESI, +ve)=515.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.41-7.30 (m, 4H), 6.83 (dd,J=16.0, 8.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.49-4.44 (m, 1H), 3.80-3.76 (m, 10H), 3.35-3.31 (m, 3H),3.32-3.28 (m, 1H), 3.10-3.06 (m, 1H).

Step 1:(S)-6-chloro-7-(4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 where6-Chloro-7-(4-fluorophenyl)-8-iodoquinazoline-2,4(1H,3H)-dione and(S)-3-mercapto-2-methoxypropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 76% yieldas a yellow solid

m/z (ESI, +ve)=411.0 (M+H)+.

Step 2:(S)-10-chloro-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(S)-6-chloro-7-(4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 61% yield as a yellow solid

m/z (ESI, +ve)=393.0 (M+H)⁺.

Step 3: tert-butyl(S)-4-(10-chloro-11-(4-fluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(S)-10-chloro-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 66% yield as a yellow solid

m/z (ESI, +ve)=561.2 (M+H)⁺.

Step 4:(S)-10-chloro-11-(4-fluorophenyl)-3-methoxy-8-(piperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(S)-4-(10-chloro-11-(4-fluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 79% yield as a yellow solid

m/z (ESI, +ve)=461.0 (M+H)+.

Example 537:(S)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-chloro-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-10-chloro-11-(4-fluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 31% yield as a yellow solid

m/z (ESI, +ve)=529.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 7.36 (d, J=8.0 Hz, 4H),6.92-6.76 (m, 1H), 6.18 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0, 4.0Hz, 1H), 4.59-4.55 (m, 1H), 4.46-4.42 (m, 2H), 4.33-3.90 (m, 3H),3.88-3.78 (m, 1H), 3.57-3.53 (m, 2H), 3.33 (s, 3H), 3.25-2.84 (m, 3H),1.29-1.25 (m, 3H).

Step 1: tert-butyl(S)-4-((S)-10-chloro-11-(4-fluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(S)-10-chloro-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (S)-3-methylpiperazine-1-carboxylate were substituted inplace of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 68% yield as a yellow solid

m/z (ESI, +ve)=575.1 (M+H)⁺.

Step 2:(S)-10-chloro-11-(4-fluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(S)-4-((S)-10-chloro-11-(4-fluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 76% yield as a yellow solid

m/z (ESI, +ve)=475.1 (M+H)+.

Example 538:(3R)-8-(4-acryloylpiperazin-1-yl)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3R)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-(piperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 36% yield as a yellow solid

m/z (ESI, +ve)=567.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.90-7.76 (m, 3H), 6.82 (dd, J=16.0, 8.0 Hz,1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0, 4.0 Hz, 1H),4.52-4.36 (m, 1H), 3.91-3.61 (m, 8H), 3.53-3.45 (m, 3H), 3.35-3.30 (m,3H), 3.20-3.09 (m, 1H).

Step 1:6-chloro-7-(5-chloro-2,4-difluorophenyl)-8-(((R)-3-hydroxy-2-methoxypropyl)thio)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 where6-chloro-7-(5-chloro-2,4-difluorophenyl)-8-iodoquinazoline-2,4(1H,3H)-dioneand (R)-3-mercapto-2-methoxypropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol in 50% yield as a yellow solid

m/z (ESI, +ve)=463.0 (M+H)⁺.

Step 2:(3R)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where6-chloro-7-(5-chloro-2,4-difluorophenyl)-8-(((R)-3-hydroxy-2-methoxypropyl)thio)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 65% yield as a yellow solid

m/z (ESI, +ve)=445.0 (M+H)⁺.

Step 3: tert-butyl4-((3R)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3R)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 78% yield as a yellow solid

m/z (ESI, +ve)=613.2 (M+H)⁺.

Step 4:(3R)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-(piperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl4-((3R)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 92% yield as a yellow solid

m/z (ESI, +ve)=513.0 (M+H)⁺.

Example 539:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

was substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 33% yield as a yellow solid

m/z (ESI, +ve)=629.1 (M+H)+.

¹H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.80-7.72 (m, 2H), 6.81 (dd,J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.80-4.30 (m, 4H), 4.15-3.98 (m, 2H), 3.92-3.80 (m, 1H),3.61-3.40 (m, 1H), 3.35 (s, 3H), 3.30-3.12 (m, 3H), 1.43-1.20 (m, 6H).

Step 1:7-(5-chloro-2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(5-chloro-2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-2-methoxybutane-1-thiol was substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 49% yieldas a white solid.

m/z (ESI, +ve)=497.0 (M+H)⁺.

Step 2:(3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(5-chloro-2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 53% yield as a yellow solid

m/z (ESI, +ve)=478.9 (M+H)⁺.

Step 3:(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where((3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 74% yield as a yellow solid

m/z (ESI, +ve)=575.0 (M+H)⁺.

Example 540:(R)-8-(4-acryloylpiperazin-1-yl)-10-chloro-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(R)-10-chloro-11-(4-fluorophenyl)-3-methoxy-8-(piperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one.The title compound was isolated in 32% yield as a yellow solid

m/z (ESI, +ve)=515.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.45-7.28 (m, 4H), 6.83 (dd,J=16.0, 8.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.49-4.45 (m, 1H), 3.86-3.66 (m, 8H), 3.34-3.29 (m, 6H),3.10-3.06 (m, 1H).

Step 1: tert-butyl(R)-4-(10-chloro-11-(4-fluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(R)-10-chloro-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 90% yield as a yellow solid

m/z (ESI, +ve)=561.1 (M+H)⁺.

Step 2:(R)-10-chloro-11-(4-fluorophenyl)-3-methoxy-8-(piperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(R)-4-(10-chloro-11-(4-fluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 88% yield as a yellow solid

m/z (ESI, +ve)=461.1 (M+H)⁺.

Example 541:(3R)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3R)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 33% yield as a yellow solid

m/z (ESI, +ve)=581.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.85-7.74 (m, 2H), 7.72-7.65 (m, 1H),6.92-6.78 (m, 1H), 6.23-6.18 (dd, J=16.0, 4.0 Hz, 1H), 5.76-5.72 (dd,J=16.0, 4.0 Hz, 1H), 4.85-4.52 (m, 2H), 4.48-4.37 (m, 2H), 4.30-4.09 (m,1H), 4.05-3.96 (m, 1H), 3.94-3.84 (m, 1H), 3.78-3.43 (m, 3H), 3.42-3.34(m, 3H), 3.25-3.17 (m, 1H), 3.08-2.86 (m, 1H), 1.31-1.15 (m, 3H).

Step 1: tert-butyl(3S)-4-((3R)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3R)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (S)-3-methylpiperazine-1-carboxylate were substituted inplace of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 65% yield as a yellow solid

m/z (ESI, +ve)=627.1 (M+H)⁺.

Step 2:(3R)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(3S)-4-((3R)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 99% yield as a yellow solid

m/z (ESI, +ve)=527.0 (M+H)⁺.

Example 542:(3R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3R)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 22% yield as a yellow solid

m/z (ESI, +ve)=595.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.84-7.73 (m, 3H), 6.80 (dd, J=16.0, 8.0 Hz,1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0, 4.0 Hz, 1H),4.65-4.36 (m, 4H), 4.09-3.98 (m, 2H), 3.92-3.83 (m, 1H), 3.52-3.45 (m,1H), 3.39-3.34 (m, 3H), 3.32-3.27 (m, 2H), 3.19-3.10 (m, 1H), 1.46-1.29(m, 6H).

Step 1:(3R)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3R)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 76% yield as a yellow solid

m/z (ESI, +ve)=541.1 (M+H)⁺.

Example 543:(3S)-8-(4-acryloylpiperazin-1-yl)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-(piperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 22% yield as a yellow solid

m/z (ESI, +ve)=567.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.87-7.72 (m, 3H), 6.82 (dd, J=16.0 Hz, 8.0Hz, 1H), 6.17 (dd, J=16.0 Hz, 4.0 Hz 1H), 5.74 (dd, J=16.0 Hz, 4.0 Hz,1H), 4.48-4.44 (m, 1H), 3.91-3.63 (m, 9H), 3.48-3.44 (m, 1H), 3.32 (s,4H), 3.21-3.09 (m, 1H).

Step 1:6-chloro-7-(5-chloro-2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-methoxypropyl)thio)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 where6-chloro-7-(5-chloro-2,4-difluorophenyl)-8-iodoquinazoline-2,4(1H,3H)-dioneand (S)-3-mercapto-2-methoxypropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol in 61% yield as a yellow solid

m/z (ESI, +ve)=462.9 (M+H)⁺.

Step 2:(3S)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where6-chloro-7-(5-chloro-2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-methoxypropyl)thio)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 58% yield as a yellow solid

m/z (ESI, +ve)=445.0 (M+H)⁺.

Step 3: tert-butyl4-((3S)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3S)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 89% yield as a yellow solid

m/z (ESI, +ve)=613.1 (M+H)⁺.

Step 4:(3S)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-(piperazin-1-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl4-((3S)-10-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 75% yield as a yellow solid

m/z (ESI, +ve)=513.0 (M+H)⁺.

Example 582:(3S)-8-(4-acryloylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

was substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 13% yield as a yellow solid

m/z (ESI, +ve)=601.1 (M+H)+.

¹H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.80-7.75 (m, 2H), 6.82 (dd,J=16.0, 8.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.50-4.48 (m, 1H), 3.84-3.74 (m, 8H), 3.51-3.35 (m, 4H),3.27-3.18 (m, 3H).

Step 1: tert-butyl4-((3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 70% yield as a yellow solid

m/z (ESI, +ve)=647.0 (M+H)⁺.

Step 2:(3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl4-((3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 91% yield as a yellow solid

m/z (ESI, +ve)=547.1 (M+H)+.

Example 583:(3S)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

was substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 41% yield as a yellow solid

m/z (ESI, +ve)=615.1 (M+H)+.

¹H NMR (400 MHz, DMSO-d6) δ 7.80-7.77 (m, 3H), 6.87-6.83 (m, 1H), 6.19(dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0, 4.0 Hz, 1H), 4.67-4.63 (m,1H), 4.49-4.41 (m, 2H), 4.28-4.15 (m, 2H), 3.99-3.85 (m, 2H), 3.59-3.36(m, 5H), 3.27-3.02 (m, 3H), 1.31 (dd, J=16.0, 4.0 Hz, 3H).

Step 1:(3S)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (S)-3-methylpiperazine-1-carboxylate were substituted inplace of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 69% yield as a yellow solid

m/z (ESI, +ve)=661.1 (M+H)⁺.

Step 2:(3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where(3S)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 90% yield as a yellow solid

m/z (ESI, +ve)=561.1 (M+H)+.

Example 584:(R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(R)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 39% yield as a yellow solid

m/z (ESI, +ve)=577.2 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.36-7.32 (m, 4H), 6.81 (dd,J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=12.0,4.0 Hz, 1H), 4.65-4.44 (m, 3H), 4.09-4.05 (m, 2H), 3.84-3.80 (m, 1H),3.35-3.30 (m, 5H), 3.28-3.24 (m, 2H), 3.11-3.07 (m, 1H), 1.40 (s, 6H).

Step 1:(R)-7-(4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 where7-(4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (R)-3-mercapto-2-methoxypropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 90% yieldas a yellow solid

m/z (ESI, +ve)=445.1 (M+H)+.

Step 2:(R)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(R)-7-(4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 82% yield as a yellow solid

m/z (ESI, +ve)=427.1 (M+H)+.

Step 3:(R)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(R)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 73% yield as a yellow solid

m/z (ESI, +ve)=523.2 (M+H)⁺.

Example 585:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 47% yield as a white solid

m/z (ESI, +ve)=577.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ=8.02 (s, 1H), 7.36-7.34 (m, 4H), 6.82 (dd,J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.59-4.48 (m, 3H), 4.09-4.05 (m, 2H), 3.84-3.82 (m, 1H),3.33-3.32 (m, 5H), 3.28-3.24 (m, 2H), 3.12-3.08 (m, 1H), 1.40 (m, 6H).

Step 1:(S)-7-(4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 where(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-oneand (S)-3-mercapto-2-methoxypropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 90% yieldas a yellow solid

m/z (ESI, +ve)=445.1 (M+H)+.

Step 2:(S)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(S)-7-(4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 72% yield as a yellow solid

m/z (ESI, +ve)=427.1 (M+H)+.

Step 3:(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(S)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 53% yield as a yellow solid

m/z (ESI, +ve)=523.1 (M+H)⁺.

Example 586:(3R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(2,4-difluorophenyl)-3-(dimethylamino)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 454, where(12R)-8-(2,4-difluorophenyl)-12-(dimethylamino)-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-7-(trifluoromethyl)-10-thia-1,3-diazatricyclo[7.4.1.05,14]tetradeca-3,5(14),6,8-tetraen-2-onewas substituted in place of(3S)-11-(2,4-difluorophenyl)-3-(methyl(2,2,2-trifluoroethyl)amino)-8-((S)-2-methylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one.The title compound was isolated in 35% yield as a white solid

m/z (ESI, +ve)=608.2

1H NMR (400 MHz, MeOD): δ 8.12 (d, J=2.1 Hz, 1H), 7.34-7.24 (m, 1H),7.13 (ddt, J=10.8, 8.4, 2.9 Hz, 2H), 6.84 (dd, J=16.7, 10.6 Hz, 1H),6.29 (dd, J=16.6, 2.1 Hz, 1H), 5.80 (dd, J=10.6, 2.0 Hz, 1H), 4.76 (dd,J=13.7, 2.5 Hz, 1H), 4.64-4.57 (m, 1H), 4.40-4.27 (m, 2H), 3.79-3.71 (m,1H), 3.65-3.58 (m, 1H), 3.53-3.41 (m, 2H), 3.21-3.10 (m, 1H), 2.64-2.48(m, 2H), 2.23 (d, J=1.9 Hz, 6H), 1.54 (dd, J=14.0, 7.0 Hz, 3H), 1.44(dd, J=13.2, 6.9 Hz, 3H).

Step 1: (2S)-1-benzyloxy-3-tritylsulfanyl-propan-2-ol

The title compound was prepared analogously to Example 454, step 1,where (2S)-2-(benzyloxymethyl)oxirane was substituted in place of(2R)-2-(benzyloxymethyl)oxirane. The title compound was isolated in 95%yield as a colorless oil

1H NMR (400 MHz, DMSO) δ 7.38-7.19 (m, 20H), 5.04 (s, 1H), 4.39 (s, 2H),3.54 (q, J=5.9 Hz, 1H), 3.25 (ddd, J=31.3, 9.8, 5.4 Hz, 2H), 2.33-2.15(m, 2H).

Step 2: [(1S)-1-(benzyloxymethyl)-2-tritylsulfanyl-ethyl]methanesulfonate

The title compound was prepared analogously to Example 454, step 2,where (2S)-2-(benzyloxymethyl)oxirane was substituted in place of(2R)-2-(benzyloxymethyl)oxirane. The title compound was isolated in 52%yield as a colorless oil

1H NMR (400 MHz, CDCl3) δ 7.45-7.42 (m, 5H), 7.34-7.24 (m, 15H),4.52-4.41 (m, 2H), 4.33 (qd, J=6.4, 4.8 Hz, 1H), 3.55-3.43 (m, 2H), 2.95(s, 3H), 2.64 (qd, J=13.4, 6.5 Hz, 2H).

Step 3: (2R)-1-benzyloxy-N,N-dimethyl-3-tritylsulfanyl-propan-2-amine

The title compound was prepared analogously to Example 454, step 3,where [(1S)-1-(benzyloxymethyl)-2-tritylsulfanyl-ethyl] methanesulfonatewas substituted in place of (R)-1-(benzyloxy)-3-(tritylthio)propan-2-ylmethanesulfonate. The title compound was isolated in 9% yield as a paleyellow oil

m/z (ESI, +ve)=468.2

Step 4: (2R)-3-Benzyloxy-2-(dimethylamino)propane-1-thiol

The title compound was prepared analogously to Example 454, step 4,where (2R)-1-benzyloxy-N,N-dimethyl-3-tritylsulfanyl-propan-2-amine wassubstituted in place of(S)-1-(benzyloxy)-N-methyl-N-(2,2,2-trifluoroethyl)-3-(tritylthio)propan-2-amine.The title compound was immediately used in the next step without furtherpurification

Step 5:8-[(2R)-3-benzyloxy-2-(dimethylamino)propyl]sulfanyl-7-(2,4-difluorophenyl)-6-(trifluoromethyl)-1H-quinazoline-2,4-dione

The title compound was prepared analogously to Example 454, step 5,where (2R)-3-Benzyloxy-2-(dimethylamino)propane-1-thiol was substitutedin place of (2R)-3-benzyloxy-2-(dimethylamino)propane-1-thiol. The titlecompound was isolated in 71% yield as a yellow semisolid

m/z (ESI, +ve)=566.1

Step 6:7-(2,4-difluorophenyl)-8-[(2R)-2-(dimethylamino)-3-hydroxy-propyl]sulfanyl-6-(trifluoromethyl)-1H-quinazoline-2,4-dione

To a solution of8-[(2R)-3-benzyloxy-2-(dimethylamino)propyl]sulfanyl-7-(2,4-difluorophenyl)-6-(trifluoromethyl)-1H-quinazoline-2,4-dione(45 mg, 0.08 mmol) in dichloromethane (1 mL) precooled at −78° C. (1mL), 0.16 mL of boron tribromide (1M in dichloromethane) was addeddropwise. The reaction was stirred at −78° C. for 1 hour and after thattime quenched by the addition of methanol (3 mL) and a small scoop ofsodium sulfite powder. The reaction was stirred at room temperature for10 minutes and diluted with 5 additional mL of methanol. The solids wereseparated by filtration and the filtrate concentrated under reducedpressure to afford the title compound which was used in the next stepwithout further purification.

m/z (ESI, +ve)=476.1

Step 7:(12R)-8-(2,4-difluorophenyl)-12-(dimethylamino)-7-(trifluoromethyl)-10-thia-1,3-diazatricyclo[7.4.1.05,14]tetradeca-5(14),6,8-triene-2,4-dione

The title compound was prepared analogously to Example 454, step 7,where7-(2,4-difluorophenyl)-8-[(2R)-2-(dimethylamino)-3-hydroxy-propyl]sulfanyl-6-(trifluoromethyl)-1H-quinazoline-2,4-dionewas substituted in place of7-(2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-(methyl(2,2,2-trifluoroethyl)amino)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.The title compound was isolated in 82% yield as a white solid

m/z (ESI, +ve)=458.2

Step 8: tert-butyl(2S,6R)-4-[(12R)-8-(2,4-difluorophenyl)-12-(dimethylamino)-2-oxo-7-(trifluoromethyl)-10-thia-1,3-diazatricyclo[7.4.1.05,14]tetradeca-3,5,7,9(14)-tetraen-4-yl]-2,6-dimethyl-piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(12R)-8-(2,4-difluorophenyl)-12-(dimethylamino)-7-(trifluoromethyl)-10-thia-1,3-diazatricyclo[7.4.1.05,14]tetradeca-5(14),6,8-triene-2,4-dioneand tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate weresubstituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 31% yield as a tan solid

m/z (ESI, +ve)=654.2

Step 9:(12R)-8-(2,4-difluorophenyl)-12-(dimethylamino)-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-7-(trifluoromethyl)-10-thia-1,3-diazatricyclo[7.4.1.05,14]tetradeca-3,5(14),6,8-tetraen-2-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2S,6R)-4-[(12R)-8-(2,4-difluorophenyl)-12-(dimethylamino)-2-oxo-7-(trifluoromethyl)-10-thia-1,3-diazatricyclo[7.4.1.05,14]tetradeca-3,5,7,9(14)-tetraen-4-yl]-2,6-dimethyl-piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 99% yield as a brown solid m/z (ESI,+ve)=554.2.

Select CAF data (see Example 7 below for assay) for various compoundsare tabulated below:

TABLE 6 CAF data for compounds 408 to 589 Example % CAF @ Number IUPACName MW 10 uM, 1 h 4087-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10- 525 39.3(5-fluoro-1H-indazol-4-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 4097-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10- 520.95 94(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 410(S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro- 611.17 83.93-((4-ethylpiperazin-1-yl)methyl)-10-(4-fluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 411(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 615.14 93.3chloro-10-(2,4-difluorophenyl)-3-((4-methylpiperazin-1-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 412(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 663.61 73.6chloro-10-(5-chloro-2,4-difluorophenyl)-3-((4-ethylpiperazin-1-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 413(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 628.18 86.6chloro-10-(2,4-difluorophenyl)-3-((1-ethylpiperidin-4-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 414(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 664.16 92chloro-3-((1-(2,2-difluoroethyl)piperidin-4-yl)methyl)-10-(2,4-difluorophenyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)-one415 (3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 656.19 85.4chloro-10-(2,4-difluorophenyl)-3-((1-(oxetan-3-yl)piperidin-4-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 416(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 647.15 91.2chloro-3-((4-ethylpiperazin-1-yl)methyl)-10-(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one417 7-(9-acryloyl-7,9-diazaspiro[bicyclo[3.3.1]nonane-3,3′- 604.59 2oxetan]-7-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 41810-(2,4-difluorophenyl)-7-(9-(2-fluoroacryloyl)-7-oxo- 594.53 583,9-diazabicyclo[3.3.1]nonan-3-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 4197-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10- 525 54.3(7-fluoro-1H-indazol-4-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 420(E)-10-(2,4-difluorophenyl)-7-(9-(4- 633.63 93(dimethylamino)but-2-enoyl)-7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-9-(trifluoromethyl)-2,3 -dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 421(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 674.18 85.1chloro-3-((1-(oxetan-3-yl)piperidin-4-yl)methyl)-10-(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 422(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 641.17 84.2chloro-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one423 (3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 614.15 34.1chloro-10-(2,4-difluorophenyl)-3-((1-methylpiperidin-4-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 424(R)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro- 646.17 13.93-((1-ethylpiperidin-4-yl)methyl)-10-(2,4,6-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one425 (S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(4- 671.75 94.7fluorophenyl)-3-((1-(oxetan-3-yl)piperidin-4-yl)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 426(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 690.63 82.8chloro-10-(5-chloro-2,4-difluorophenyl)-3-((1-(oxetan-3-yl)piperidin-4-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 4277-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10- 519.42 63.5(2-chloro-4-fluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 428(S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-3-((1- 679.72 79.6(2,2-difluoroethyl)piperidin-4-yl)methyl)-10-(4-fluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 429(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-3-((1- 729.71 61(2,2-difluoroethyl)piperidin-4-yl)methyl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 1,1-dioxide 430(S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(4- 722.68 90.9fluorophenyl)-9-(trifluoromethyl)-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 431(3S)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-11-(2,4- 566.54 90difluorophenyl)-3-hydroxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6- one 432(3R)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 616.12 2.6chloro-10-(2,4-difluorophenyl)-3-(((1-ethylazetidin-3-yl)oxy)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one433 7′-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9′-chloro-10′- 529 25.3(2,4-difluorophenyl)-3′H,5′H-spiro[cyclopropane-1,2′-[1,4]thiazino[2,3,4-ij]quinazolin]-5′-one 434(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(2,4- 693.73 51.5difluorophenyl)-3-((1-ethylpiperidin-4-yl)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 1,1-dioxide 435(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(2,4- 580.57 95.8difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 436(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(2,4- 612.57 72.5difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 1,1-dioxide 437(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(2,4- 634.66 95.7difluorophenyl)-3-((tetrahydro-2H-pyran-4-yl)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 438(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 601.11 92.8chloro-10-(2,4-difluorophenyl)-3-((tetrahydro-2H-pyran-4-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 439 (E)-7-(9-(4,4-difluorobut-2-enoyl)-7-oxo-3,9-626.55 97 diazabicyclo[3.3.1]nonan-3-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino [2,3,4-ij]quinazolin-5-one 440 (E)-10-(2,4-difluorophenyl)-7-(7-oxo-9-(4,4,4-644.54 96 trifluorobut-2-enoyl)-3,9-diazabicyclo[3.3.1]nonan-3-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 4417-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10- 536.02 78.5(5-fluoroquinolin-8-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 442(2S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(2,4- 593.61 87difluorophenyl)-2-((dimethylamino)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 443(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 730.71 48.23-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-9-(trifluoromethyl)-10-(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 444(S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro- 689.13 24.110-(4-fluorophenyl)-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 445(S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 703.15 68.29-chloro-10-(4-fluorophenyl)-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 446(3R)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 611.49 38chloro-10-(5-chloro-2,4 -difluorophenyl)-3-((methoxymethoxy)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 447(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 741.56 63.3chloro-10-(5-chloro-2,4-difluorophenyl)-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 448(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 755.59 559-chloro-10-(5-chloro-2,4-difluorophenyl)-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 449(3S)-3-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-7- 690.63 51.6((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 4508-((S)-4-acryloyl-2-methylpiperazin-1-yl)-11-(2,4- 550.54 61difluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 45111-(2,4-difluorophenyl)-8-(9-(2-fluoroacryloyl)-7-oxo- 608.55 613,9-diazabicyclo[3.3.1]nonan-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 452(E)-7-(9-(but-2-enoyl)-7-oxo-3,9- 590.56 63diazabicyclo[3.3.1]nonan-3-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 4537-(9-(but-2-ynoyl)-7-oxo-3,9-diazabicyclo[3.3.1]nonan- 373-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 454(3S)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-11-(2,4- 661.61 61difluorophenyl)-3-(methyl(2,2,2-trifluoroethyl)amino)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 455(S)-8-(4-acryloyl-2-methylpiperazin-1-yl)-10- 534.98 21(trifluoromethyl)-11-(2,4,6-trifluorophenyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6- one 456(3S)-3-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-7- 676.6 77.6((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 457(3S)-3-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-7- 699.59 76.8((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 458(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 675.62 55.6chloro-10-(5-chloro-2,4-difluorophenyl)-3-((4-cyclopropylpiperazin-1-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 459(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 739.13 82.2chloro-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-10-(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 460(3S)-3-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-7- 674.18 79.7((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-9-chloro-10-(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 461(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 712.63 79.59-chloro-10-(5-chloro-2,4-difluorophenyl)-3-((1-(2,2-difluoroethyl)piperidin-4-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 462(S)-3-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-7-((S)- 624.17 87.84-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10-(4-fluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one463 (3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 725.11 69chloro-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-10-(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 464(3S)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-11-(2,4- 580.57 95difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6- one 465(3R)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-11-(2,4- 580.57 96difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6- one 466(3R)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 595.03 22.6chloro-3-((methoxymethoxy)methyl)-10-(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one467 (3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 688.66 44.39-chloro-10-(5-chloro-2,4-difluorophenyl)-3-((1-cyclopropylpiperidin-4-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 468(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 721.14 68.69-chloro-10-(2,4-difluorophenyl)-3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 469(3S)-3-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-7- 660.15 57.8((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10-(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 470(3R)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(5- 645.04 35chloro-2,4-difluorophenyl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 471(3R)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-3- 628.59 23.9((methoxymethoxy)methyl)-9-(trifluoromethyl)-10-(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 472(3S)-3-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-7- 642.16 72.3((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 473(S)-3-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-7- 638.2 65.8((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-9-chloro-10-(4-fluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 474(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 580.07 73.3chloro-10-(5-fluoroquinolin-8-yl)-3-(methoxymethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 475(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 672.2 49.89-chloro-3-((1-cyclopropylpiperidin-4-yl)methyl)-10-(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 476(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 696.17 53.89-chloro-3-((1-(2,2-difluoroethyl)piperidin-4-yl)methyl)-10-(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 477(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 678.18 63.59-chloro-3-((1-(2,2-difluoroethyl)piperidin-4-yl)methyl)-10-(2,4-difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 478(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 654.21 70.79-chloro-3-((1-cyclopropylpiperidin-4-yl)methyl)-10-(2,4-difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 479(3R)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 577.04 42chloro-10-(2,4-difluorophenyl)-3-((methoxymethoxy)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 480(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 683.13 61.2chloro-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-10-(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 481(S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 665.69 59.43-((1-(2,2-difluoroethyl)azetidin-3-yl)methyl)-10-(4-fluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 482(3S,10S)-3-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)- 676.6 907-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 483(3S,10R)-3-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)- 676.6 15.77-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 484(3S,10S)-3-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)- 674.18 77.97-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-9-chloro-10-(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 485(3S,10R)-3-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)- 674.18 457-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-9-chloro-10-(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 4868-(9-acryloyl-7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)- 590.56 9511-(2,4-difluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6- one 487(3S)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10- 547.02 96chloro-11-(2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 488(3R)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10- 547.02 96chloro-11-(2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 489(3S)-8-(4-acryloylpiperazin-1-yl)-11-(2,4- 566.54 96difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6- one 490(3R)-8-(4-acryloylpiperazin-1-yl)-11-(2,4- 566.54difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6- one 491(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 612.59 603-(methoxymethyl)-9-(trifluoromethyl)-10-(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one492 (3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 629.04 63.210-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 493(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 594.6 78.610-(2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 494(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 561.04 68.79-chloro-10-(2,4-difluorophenyl)-3-(methoxymethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 495(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 713.62 50.89-chloro-10-(5-chloro-2,4-difluorophenyl)-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 496(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 595.49 65.39-chloro-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one497 (S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 576.61 85.110-(4-fluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 498(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 638.65 81.210-(2,4-difluorophenyl)-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 499(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 689.65 289-chloro-10-(5-chloro-2,4-difluorophenyl)-3-((4-cyclopropylpiperazin-1-yl)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 500(3S)-3-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5- 662.58 50.6yl)methyl)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-9-chloro-10-(5-chloro-2,4-difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one501 (3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 605.1 66.89-chloro-10-(2,4-difluorophenyl)-3-((2-methoxyethoxy)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 502(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 639.54 65.19-chloro-10-(5-chloro-2,4-difluorophenyl)-3-((2-methoxyethoxy)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 503(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)- 594.6 9611-(2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 504(3S)-8-(4-acryloylpiperazin-1-yl)-10-chloro-11-(2,4- 532.99 96difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 505(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)- 561.04 9510-chloro-11-(2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6- one 506(3S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)- 579.03 17.59-chloro-3-(methoxymethyl)-10-(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 507(2S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(2,4- 580.57 71difluorophenyl)-2-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 508(3S,10S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin- 594.6 921-yl)-10-(2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 509(3S,10R)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin- 594.6 96.51-yl)-10-(2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 510(3S,10S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin- 638.65 72.91-yl)-10-(2,4-difluorophenyl)-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 511(3S,10R)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin- 638.65 80.61-yl)-10-(2,4-difluorophenyl)-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 512S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 620.66 66.110-(4-fluorophenyl)-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 513(3S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)- 594.6 96.210-(2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 514 (3S)-7-(4-acryloylpiperazin-1-yl)-10-(2,4-566.54 96.1 difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 515(S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 661.18 55.19-chloro-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-10-(4-fluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 516(S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(4- 592.6 74.4fluorophenyl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 517(S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 637.21 59.59-chloro-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(4-fluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one518 (3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10-(5- 645.04chloro-2,4-difluorophenyl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 519(3S)-3-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5- 628.13 61.3yl)methyl)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-9-chloro-10-(2,4-difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one520 (3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-9- 659.16 51.1chloro-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 521(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 747.17 40.610-(5-chloro-2,4-difluorophenyl)-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 522(3S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-3- 628.59 72.4((methoxymethoxy)methyl)-9-(trifluoromethyl)-10-(2,4,5-trifluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 523(3S)-7-(9-acryloyl-7,7-difluoro-3,9- 642.59 68.9diazabicyclo[3.3.1]nonan-3-yl)-10-(2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 524(3R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)- 594.6 9511-(2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 525(3R)-8-(4-acryloylpiperazin-1-yl)-10-chloro-11-(2,4- 532.99 86difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 526(3R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)- 561.04 9310-chloro-11-(2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6- one 527(R)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-11-(4- 562.58 97fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6- one 528(R)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10- 529.03 98chloro-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 529(3S)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10- 581.46 95chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6- one 530(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)- 595.49 9210-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin- 6-one 5318′-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11′- 606.61 88.6(2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]- 6′-one 532(S)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-11-(4 - 562.58 97fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6- one 533(3R)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-11-(5- 615.01 96chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 534(3R)-8-(4-acryloylpiperazin-1-yl)-11-(5-chloro-2,4- 600.99 97difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6- one 535(3R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)- 629.04 9611-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 536(S)-8-(4-acryloylpiperazin-1-yl)-10-chloro-11-(4- 515 97fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 537(S)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10- 529.03 96chloro-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 538(3R)-8-(4-acryloylpiperazin-1-yl)-10-chloro-11-(5- 567.43 97chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 539(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)- 9611-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 540(R)-8-(4-acryloylpiperazin-1-yl)-10-chloro-11-(4- 98fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 541(3R)-8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10- 96chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6- one 542(3R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)- 9610-chloro-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin- 6-one 543(3S)-8-(4-acryloylpiperazin-1-yl)-10-chloro-11-(5- 97chloro-2,4-difluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 544(3S,10S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin- 629.04 48.81-yl)-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 545(3S,10R)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin- 629.04 94.11-yl)-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 546(3S,10S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin- 594.6 94.31-yl)-10-(2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 547(3S,10R)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin- 594.6 96.71-yl)-10-(2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 548(3S,10R)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10- 610.6 95.7(2,4-difluorophenyl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 549(3S,10S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10- 610.6 80.2(2,4-difluorophenyl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 550(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 679.17 91.69-chloro-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 551(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 655.2 53.49-chloro-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 552(3S,10R)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10- 645.04 62.2(5-chloro-2,4-difluorophenyl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 553(3S,10S)-7-((S)-4-acryloyl-2-methylpiperazin-1-yl)-10- 645.04 37(5-chloro-2,4-difluorophenyl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 554(3S,10S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin- 673.09 11.31-yl)-10-(5-chloro-2,4 -difluorophenyl)-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 555(3S,10R)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin- 673.09 67.61-yl)-10-(5-chloro-2,4 -difluorophenyl)-3-((2-methoxyethoxy)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 556(3S,10R)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin- 747.17 73.11-yl)-10-(5-chloro-2,4-difluorophenyl)-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 557(3S,10S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin- 747.17 21.21-yl)-10-(5-chloro-2,4-difluorophenyl)-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 558(S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 587.11 64.39-chloro-10-(4-fluorophenyl)-3-((2-methoxyethoxy)methyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 559(3S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)- 629.04 83.810-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 560(3S)-3-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5- 661.69 95.6yl)methyl)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 561 2-(4-(((3S)-7-((2S,5R)-4-acryloyl-2,5- 687.7310.4 dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperazin-1-yl)acetonitrile 562(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 712.72 83.63-((4-(2,2-difluoroethyl)piperazin-l-yl)methyl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 563(3S,10R)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin- 629.04 93.9 l-yl)-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 564(3S,10S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin- 629.04 80.81-yl)-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 565(3S,10S)-3-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)- 724.18 48.37-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4 -ij]quinazolin-5-one 566(3S,10R)-3-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)- 724.18 77.77-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 567(3S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)- 659.07 64.410-(5-chloro-2,4-difluorophenyl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 568(3S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)- 615.01 52.310-(5-chloro-2,4-difluorophenyl)-3-(hydroxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 569(3S,10R)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin- 697.24 93.4 l-yl)-9-chloro-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-10-(1-methyl-1H-indazol-7 -yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 570(3S,10S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin- 697.24 01-yl)-9-chloro-3-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-10-(1-methyl-1H-indazol-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 571(3S)-7-(9-acryloyl-7-oxo-3,9-diazabicyclo[3.3.1]nonan- 620.59 95.23-yl)-10-(2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 572(3S)-7-(4-acryloylpiperazin-1-yl)-10-(5-chloro-2,4- 600.99 93.6difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 573(S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)- 543.05 76.49-chloro-10-(4-fluorophenyl)-3-(methoxymethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 574S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-3- 694.73 83.2((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-10-(4-fluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 5752-(4-(((3S)-7-((2S,5R)-4-acryloyl-2,5- 705.74 89.5dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperazin-1-yl)acetamide 576(3S,10S)-3-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)- 689.74 80.57-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 577(3S,10R)-3-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)- 689.74 74.87-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 578(3S,10R)-7-(4-acryloylpiperazin-1-yl)-10-(2,4- 566.54 98difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 579(3S,10S)-7-(4-acryloylpiperazin-1-yl)-10-(2,4- 566.54 96.9difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 580(3S,10S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin- 688.75 91.51-yl)-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 581(3S,10R)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin- 688.75 97.41-yl)-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 582(3S)-8-(4-acryloylpiperazin-1-yl)-11-(5-chloro-2,4- 600.99 88difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6- one 583(3S)-8-((S)-4-acryloyl-2-methylpiperazin-l-yl)-11-(5- 615.01 91chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 584(R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)- 576.61 9711-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin- 6-one 585(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)- 576.61 9711-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin- 6-one 586(3R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)- 607.64 4011-(2,4-difluorophenyl)-3-(dimethylamino)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one 587(3S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)- 58.910-(5-chloro-2,4-difluorophenyl)-3-((dimethylamino)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one 5888′-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-11′- 607.18 95.9(2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]- 6′-one 5898′-(4-acryloylpiperazin-1-yl-2,2,3,3,5,5,6,6-d8)-11′-(2,4- 587.2 92.9difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]- 6′-one

In embodiments, there also provided the following further compounds:

It will be appreciated by those skilled in the art that the compoundsabove possess chiral centers as well potential axial asymmetry, i.e.,atropisomers. Each of the compounds may be provided as a mixture ofdiastereomers or in any diastereomerically pure form. Representativeexperimental examples of the above follow.

Example 1139 and 1140(3S,10S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(P1) and(3S,10R)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(P2)

(R)-1-mercapto-3-methoxypropan-2-ol (2)

To a mixture of (S)-2-(methoxymethyl)oxirane (50 g, 568.2 mmol) intetrahydrofuran (800 mL) was added 1,1,1,3,3,3-hexamethyldisilathiane(119.4 g, 681.8 mmol) and tetrabutylammonium fluoride (1.0 M intetrahydrofuran, 170.6 mL, 170.5 mmol) at 0° C. The mixture was stirredat room temperature for 2 hours. After completion, the mixture waspoured into water (3000 mL), extracted with ethyl acetate (3×800 mL).The combined organic phases were washed with brine (800 mL) and driedover anhydrous sodium sulfate. After filtration and concentration, theresidue was purified by silica gel column with petroleum ether/ethylacetate=3/1 to afford (R)-1-mercapto-3-methoxypropan-2-ol (70.0 g,crude) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 3.86-3.82 (m, 1H),3.49-3.46 (m, 1H), 3.41-3.37 (m, 4H), 2.71-2.64 (m, 1H), 1.55-1.50 (m,1H).

(R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(4)

To a solution of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2) (20g, 51.2 mmol) in dioxane (800 mL), potassium carbonate (21.2 g, 153.6mmol), (R)-1-mercapto-3-methoxypropan-2-ol (11.26 g, 92.1 mmol),4,5-Bis(diphenyl-phosphino)-9,9-dimethylxanthene (5.93 g, 10.24 mmol)and Tris(dibenzylideneacetone) dipalladium (4.7 g, 5.1 mmol) were added.The mixture was stirred at 55° C. under nitrogen atmosphere for 18hours. After completion, the insoluble was filtered out. Afterconcentration, the residue was adjusted to pH=4 with acetic acid andextracted with ethyl acetate (1000 mL), washed with brine (500 mL). Theorganic phase was concentrated and recrystallized(dichloromethane/methanol=1/10). The mixture was filtered and collectedfilter cake to afford(R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(14 g, yield: 71%) as a white solid. MS (ESI) m/z 385.0 [M+H]⁺.

(S)-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(5)

To a mixture of(R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(34.4 g, 89.5 mmol) and triphenylphosphoranylidene (35.2 g, 134.3 mmol)in tetrahydrofuran (500 mL) was added diethyl azodicarboxylate (23.3 g,134.3 mmol) at 0° C. The mixture was stirred at 0° C. for 45 min. Aftercompletion, the mixture was poured into ice-water (300 mL) and extractedwith ethyl acetate (3×500 mL). After concentration, the residue wasrecrystallized (dichloromethane/methanol=1/10). The mixture was filteredand collected filter cake to afford(S)-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(5) (24.0 g, 73% yield) as a white solid. MS (ESI): m/z 367.0 [M+H]⁺.

(2S,6R)-tert-butyl4-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6)

To a mixture of(S)-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(5) (10 g, 27.32 mmol) and potassium carbonate (37.7 g, 273.2 mmol) inacetonitrile (500 mL) was added 4-methylbenzenesulfonic anhydride (13.4g, 40.98 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min andat 30° C. for 4 hours. After completion, (2S,6R)-tert-butyl2,6-dimethylpiperazine-1-carboxylate (11.7 g, 54.64 mmol) was added intothe reaction solution. The reaction mixture was stirred at 0° C. for 2hour. After completion, the mixture was filtered through a Celite pad.After concentration, the residue was purified by chromatography column(dichloromethane/methanol=100/1 to 30/1) to afford (2S,6R)-tert-butyl4-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6) (15 g, crude) as a pale-white solid. MS (ESI) m/z 563.5 [M+H]⁺.

(2S,6R)-tert-butyl4-((3S)-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(7)

To a solution of (2S,6R)-tert-butyl4-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(40 g, 71.0 mmol) in 1,4-dioxane (500 mL) and water (50 mL),tripotassium phosphate (16.9 g, 213 mmol),(5-chloro-2,4-difluorophenyl)boronic acid (24.4 g, 142 mmol), andChloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(8.27 g, 10.7 mmol) were added. The mixture was stirred at 85° C. undernitrogen atmosphere for 4 hours. After completion, the mixture wasdiluted with tetrahydrofuran (3 L) and the insoluble was filtered out.After concentration, the residue was purified by silica gel columnchromatography (dichloromethane/methanol=100/1 to 30/1) to afford((2S,6R)-tert-butyl4-((3S)-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(7) (45 g, crude) as a yellow solid. MS (ESI) m/z 674.6 [M+H]⁺.

(3S)-10-(5-chloro-2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a cooled mixture of (((2S,6R)-tert-butyl4-((3S)-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(45 g, 71.0 mmol) in dichloromethane (300 ml) was added trifluoroaceticacid (100 mL) at 0° C. The reaction solution was stirred at roomtemperature for 3 hours. After completion, the mixture was concentrated.The residue was redissolved in dichloromethane and washed with saturatedNaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by column (dichloromethane/methanol=15:1) to afford(3S)-10-(5-chloro-2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8) (25 g, yield: 62%) as a yellow solid. MS (ESI) m/z 575.6 [M+H]⁺.

(3S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9)

To a mixture of(3S)-10-(5-chloro-2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8) (25 g, 43.6 mmol) and triethyl amine (13.2 g, 130 mmol) indichloromethane (300 ml) was added acrylic anhydride (8.23 g, 65.3 mmol)at 0° C. The mixture was stirred at 0° C. for 3 hours. After completion,the mixture was poured into ice-water (800 mL) and extracted with ethylacetate (3×800 mL). After concentration, the residue was purified bychromatography column (dichloromethane/methanol=60/1 to 30/1) to afford(3S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9) (14 g, yield: 52%) as a white solid. MS (ESI) m/z 629.6 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.28-7.24 (m, 1H), 7.09-7.04 (m,1H), 6.65-6.59 (m, 1H), 6.40 (dd, J=1.6 Hz, 16.8 Hz, 1H), 5.77 (dd,J=1.6 Hz, 10.8 Hz, 1H), 5.50-5.43 (m, 1H), 4.75-4.59 (m, 2H), 4.21-4.15(m, 2H), 3.67-3.62 (m, 2H), 3.41-3.30 (m, 6H), 3.05-3.01 (m, 1H),1.62-1.61 (m, 3H), 1.49-1.46 (m, 3H).

The above diastereomers (14 g) were dissolved with EtOH (1500 mL),separated by chiral Prep. HPLC (separation condition: Column: ChiralpakAS-H 5 μm 20×250 mm; Mobile Phase: CO₂:EtOH=70:30 at 25 mL/min; Temp:25° C.; Wavelength: 254 nm) to afford the title compounds P1 (7.62 g,54% yield, 100% de), and P2 (4.25 g, 30% yield, 98.1% de); Chiral HPLCAnalytical: on CHIRALPAK® AS-H was using 5 μm 4.6×250 mm column, MobilePhase: CO₂:EtOH=70:30 at 2.5 mL/min; Temp: 25° C.; Wavelength: 254 nm).

P1: ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.28-7.24 (m, 1H), 7.07 (t,J=8.8 Hz, 1H), 6.65-6.59 (m, 1H), 6.40 (dd, J=1.6 Hz, 16.8 Hz, 1H), 5.77(dd, J=1.2 Hz, 10.0 Hz, 1H), 5.45-5.44 (m, 1H), 4.73-4.58 (m, 2H),4.21-4.15 (m, 2H), 3.67-3.64 (m, 2H), 3.41-3.31 (m, 6H), 3.05-3.01 (m,1H), 1.61 (m, J=6.8 Hz, 3H), 1.47 (d, J=6.8 Hz, 3H); Chiral HPLCAnalytical: on AD-H was using 4.6×150 mm column, Mobile Phase:CO₂:EtOH=70:30 at 2.5 mL/min; Temp: 25° C.; Wavelength: 254 nm), Peak 1:e.e.=100%, Rt=3.76 min.

P2: ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.28-7.25 (m, 1H), 7.07 (t,J=8.8 Hz, 1H), 6.65-6.59 (m, 1H), 6.40 (dd, J=1.6 Hz, 16.4 Hz, 1H), 5.77(dd, J=1.6 Hz, 10.4 Hz, 1H), 5.48-5.45 (m, 1H), 4.76-4.59 (m, 2H),4.21-4.16 (m, 2H), 3.68-3.59 (m, 2H), 3.39-3.30 (m, 6H), 3.04-3.00 (m,1H), 1.61-1.59 (m, 3H), 1.46 (d, J=6.4 Hz, 3H); Chiral HPLC Analytical:on AD-H was using 4.6×150 mm column, Mobile Phase: CO₂:EtOH=70:30 at 2.5mL/min; Temp: 25° C.; Wavelength: 254 nm), Peak 2: e.e.=98.1%, Rt=4.30min.

Example 1103(S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

(2S,6R)-tert-butyl4-((S)-10-(4-fluorophenyl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(2)

To a solution of (2S,6R)-tert-butyl4-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(1) (8.0 g, 14.2 mmol) in 1,4-dioxane (200 mL) and water (25 mL),tripotassium phosphate (18.9 g, 71 mmol), (4-fluorophenyl)boronic acid(9.94 g, 71 mmol), and Chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(2.2 g, 2.84 mmol) were added. The mixture was stirred at 85° C. undernitrogen atmosphere for 4 hours. After completion, the mixture wasdiluted with tetrahydrofuran (3 L) and the insoluble was filtered out.After concentration, the residue was purified by silica gel columnchromatography (dichloromethane/methanol=100/1 to 30/1) to afford(2S,6R)-tert-butyl4-((S)-10-(4-fluorophenyl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(13 g, crude) as a yellow solid. MS (ESI) m/z 623.4 [M+H]⁺.

(S)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(3)

To a cooled mixture of (2S,6R)-tert-butyl4-((S)-10-(4-fluorophenyl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(13 g, 20.9 mmol) in dichloromethane (200 ml) was added trifluoroaceticacid (60 mL) at 0° C. The reaction solution was stirred at roomtemperature for 3 hrs. After completion, the mixture was concentrated.The residue was redissolved in dichloromethane and washed with saturatedNaHCO3. The organic layer was dried over Na2SO4 and concentrated. Theresidue was purified by column (dichloromethane/methanol=15:1) to afford(S)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(3) (5.14 g, yield: 47%) as a yellow solid. MS (ESI) m/z 523.4 [M+H]⁺.

(S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(4)

To a mixture of(S)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5.14 g, 9.84 mmol) and triethyl amine (2.98 g, 29.5 mmol) indichloromethane (100 ml) was added acrylic anhydride (1.48 g, 11.8 mmol)at 0° C. The mixture was stirred at 0° C. for 3 h. After completion, themixture was poured into ice-water (100 mL) and extracted with ethylacetate (100 mL×3). Concentrated and the residue was purified bychromatography column (dichloromethane/methanol=60/1 to 30/1) to afford(S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(4) (3.3 g yield: 58%) as a white solid. MS (ESI) m/z 577.4 [M+H]+.

1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.23-7.15 (m, 4H), 6.66-6.59 (m,1H), 6.40 (dd, J=16.8 Hz, J=1.6 Hz, 1H), 5.77 (dd, J=10.4 Hz, J=2.0 Hz,1H), 5.47-5.42 (m, 1H), 4.84-4.51 (m, 2H), 4.21-4.16 (m, 2H), 3.70-3.57(m, 2H), 3.43-3.22 (m, 6H), 2.96 (dd, J=3.2 Hz, J=2.8 Hz, 1H), 1.62 (d,J=7.2 Hz, 3H), 1.47 (d, J=7.2 Hz, 3H).

Example 11048-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(2,4-difluorophenyl)-1′-ethyl-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-azetidin]-6(4H)-one

Benzyl 3-(bromomethyl)-3-(hydroxymethyl)azetidine-1-carboxylate (2)

To a solution of benzyl 2-oxa-6-azaspiro[3.3]heptane-6-carboxylate (9.4g, 40.3 mmol) in DCM (100 mL) was added HBr (48% in AcOH; 60.5 mL)dropwise over 20 min. After completion, the resulting mixture wasquenched with Saturated ammonium chloride aqueous solution. The aqueouslayer was extracted with DCM (2×100 mL), and the combined organic layerwas washed with brine, dried over anhydrous sodium sulfate andconcenrated. The residue was purified by silica column (with 0.2%-1%methanol in dichloromethane) to afford product (2) (9.7 g, 30.9 mmol) aspale-yellow oil. MS (ESI) m/z 314.0, 316.0 [M+H]⁺.

Benzyl 3-(hydroxymethyl)-3-(mercaptomethyl)azetidine-1-carboxylate (3)

To a solution of benzyl3-(bromomethyl)-3-(hydroxymethyl)azetidine-1-carboxylate (2) (2.5 g, 7.9mmol) in ethanol (25 mL) was added sodium hydrosulfide (885 mg, 15.8mmol, 70% purity) at 0° C. The mixture was stirred at room temperatureunder nitrogen atmosphere for 5 hours. After completion, the mixture wasfiltered and concentrated. The residue was purified by silica gel columnwith dichloromethane/methanol=100/1 to afford the product (3) (1.43 g,yield: 59%) as a pale-yellow oil.

Benzyl3-(((7-chloro-2,4-dioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-8-yl)thio)methyl)-3-(hydroxymethyl)azetidine-1-carboxylate(5)

To a solution of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (3)(1.35 g, 3.5 mmol) in dioxane (20 mL) were added potassium carbonate(1.5 g, 10.5 mmol), benzyl3-(hydroxymethyl)-3-(mercaptomethyl)azetidine-1-carboxylate (1.4 g, 5.0mmol), 4,5-Bis(diphenyl-phosphino)-9,9-dimethylxanthene (578 mg, 1 mmol)and tris(dibenzylideneacetone) dipalladium (685 mg, 0.75 mmol). Themixture was stirred at 65° C. under nitrogen atmosphere for 16 hours.After completion, the mixture was filtered and the solid was washed withdichloromethane (10 mL). After concentration, the residue was purifiedby silica gel column with dichloromethane/methanol=100/1 to afford theproduct (5) (1.1 g, crude) as a pale yellow solid. MS (ESI) m/z 530.1[M+H]⁺.

Benzyl11-chloro-6,8-dioxo-10-(trifluoromethyl)-4,6,7,8-tetrahydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-azetidine]-1′-carboxylate (6)

To a mixture of benzyl3-(((7-chloro-2,4-dioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-8-yl)thio)methyl)-3-(hydroxymethyl)azetidine-1-carboxylate(1.1 g, 2.07 mmol) and tributylphosphine (0.811 g, 3.11 mmol) intetrahydrofuran (20 mL) was added diethyl azodicarboxylate (0.54 g, 3.11mmol) at 0° C. under nitrogen atmosphere. The mixture was stirred atroom temperature for 3 hours. After completion, the mixture was pouredinto ice-water (2 L) and extracted with ethyl acetate (3×2 L). Theorganic solvent was removed under vacuum, and the residue was purifiedby silica column (with 0.2%-1% methanol in dichloromethane) to affordthe crude product (6) (670 mg, yield: 67%) as a pale yellow solid. MS(ESI) m/z 512.1 [M+H]+.

Benzyl8-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-11-chloro-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-azetidine]-1′-carboxylate(7)

To a mixture of benzyl11-chloro-6,8-dioxo-10-(trifluoromethyl)-4,6,7,8-tetrahydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-azetidine]-1′-carboxylate(6) (600 mg, 1.13 mmol) and potassium carbonate (470 mg, 3.4 mmol) inmixed solvent of acetonitrile (10 mL) and dichloromethane (10 mL) wasadded 4-Methylbenzenesulfonic anhydride (552 mg, 1.69 mmol) at 25° C.The mixture was stirred at 25° C. for 6 hours. (2S,6R)-tert-butyl2,6-dimethylpiperazine-1-carboxylate (726 mg, 3.40 mmol) was added intothe reaction solution. The reaction mixture was stirred at 25° C. for 1hour. After completion, the mixture was poured into ice-water (600 mL)and extracted with ethyl acetate (3×600 mL). The organic solvent wasremoved under vacuum. The residue was purified by flash silica column(with 0.2%-1% methanol in dichloromethane) to afford the product (7)(565 mg, yield: 70%) as a yellow solid. MS (ESI) m/z 708.2 [M+H]⁺.

Benzyl8-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-11-(2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-azetidine]-1′-carboxylate(8)

To a solution of benzyl8-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-11-chloro-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-azetidine]-1′-carboxylate(450 mg, 0.64 mmol) in a solution of 1,4-dioxane (5 mL) and water (1 mL)were added tripotassium phosphate (407 mg, 1.92 mmol),(2,4-difluorophenyl)boronic acid (505 mg, 3.26 mmol), andChloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(39 mg, 0.06 mmol). The mixture was stirred at 80° C. under nitrogenatmosphere for 2 hours. After completion, the mixture was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (dichloromethane/methanol=20/1) to afford the product (8)(520 mg, crude) as a yellow solid. MS (ESI) m/z 786.3 [M+H]⁺.

(2S,6R)-tert-butyl4-(11-(2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-azetidin]-8-yl)-2,6-dimethylpiperazine-1-carboxylate(9)

To a solution of benzyl8-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-11-(2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-azetidine]-1′-carboxylate(8) (520 mg, crude) in methanol (10 mL) was added Pd/C (100 mg, 50% w/w)at room temperature. The mixture was stirred at room temperature underhydrogen atmosphere for 1 hour. After completion, the mixture wasfiltered and concentrated to afford crude product (9) (315 mg, crude) asa yellow solid which can used in next step without further purification.MS (ESI) m/z 652.2 [M+H]⁺.

(2S,6R)-tert-butyl4-(11-(2,4-difluorophenyl)-1′-ethyl-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-azetidin]-8-yl)-2,6-dimethylpiperazine-1-carboxylate(10)

To a mixture of (2S,6R)-tert-butyl4-(11-(2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-azetidin]-8-yl)-2,6-dimethylpiperazine-1-carboxylate(9) (315 mg, 0.54 mmol) in methanol (5 mL) was added sodiumcyanoborohydride (51 mg, 0.81 mmol). The mixture was stirred at 20° C.for 2 hours. After completion, the mixture was concentrated underreduced pressure, the residue was purified by silica gel columnchromatography (dichloromethane/methanol=20/1) to afford the product(10) (281 mg, 0.46 mmol) as a yellow solid. MS (ESI) m/z 680.3 [M+H]⁺.

8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(2,4-difluorophenyl)-1′-ethyl-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-azetidin]-6(4H)-one(11)

To a solution of (2S,6R)-tert-butyl4-(11-(2,4-difluorophenyl)-1′-ethyl-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-azetidin]-8-yl)-2,6-dimethylpiperazine-1-carboxylate(10) (281 mg, 0.46 mmol) in dichloromethane (4 mL) was addedtrifluoroacetic acid (1 mL) at 0° C. The reaction solution was stirredat room temperature for 1 hour. After completion, the mixture wasconcentrated. The residue was redissolved in dichloromethane and washedwith saturated NaHCO₃. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel columnchromatography (dichloromethane/methanol=15/1) to afford the product(154 mg, 0.3 mmol) as a yellow solid. MS (ESI) m/z 580.2 [M+H]⁺.

To a mixture of above product (154 mg, 0.30 mmol) and triethyl amine (90mg, 0.90 mmol) in dichloromethane (5 mL) was added acrylic anhydride (57mg, 0.45 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour.After completion, the mixture was poured into ice-water (50 mL) andextracted with ethyl acetate (3×20 mL). After concentration, the residuewas purified by preparative high performance liquid chromatography (20%to 95% acetonitrile in water) to afford the product (11) (28 mg, yield:15%) as a white solid. MS (ESI) m/z 634.2 [M+H]; ¹H NMR (400 MHz, CDCl₃)δ 8.11 (s, 1H), 7.21-7.15 (m, 1H), 7.09-6.96 (m, 2H), 6.71-6.62 (m, 1H),6.48-6.42 (m, 1H), 5.82 (dd, J=14.0 Hz, 2.4 Hz, 1H), 4.70-4.65 (m, 4H),4.21-4.18 (m, 2H), 3.55-3.31 (m, 8H), 2.67-2.61 (m, 2H), 1.58-1.50 (m,6H), 1.05 (t, J=7.2 Hz, 3H).

Example 1109 and 1110(S)-8′-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-11′-(2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one(P1) and(R)-8′-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-11′-(2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one(P2)

(3-(mercaptomethyl)oxetan-3-yl)methanol (2)

To a solution of (3-(bromomethyl)oxetan-3-yl)methanol (200 g, 1.105mmol) in ethanol (1.8 L) was added sodium hydrosulfide (176.8 g, 2.210mmol, 70% purity) at 0° C. The mixture was stirred at room temperatureunder nitrogen atmosphere for 2 hours. After completion, the mixture wasfiltered and the filtrate was concentrated to afford the crude productwhich was purified by silica gel column withdichloromethane/methanol=100/1 to afford (3-(mercaptomethyl)oxetan-3-yl)methanol (64.2 g, yield: 43%) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 4.49-4.41 (m, 4H), 3.95 (s, 2H), 2.96 (d,J=8.4 Hz, 2H), 2.06 (brs, 1H), 1.36 (t, J=8.4 Hz, 1H).

7-chloro-8-(((3-(hydroxymethyl)oxetan-3-yl)methyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(4)

To a solution of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (3)(71.40 g, 182.85 mmol) in dioxane (2200 mL) were added potassiumcarbonate (75.82 g, 548.56 mmol),(3-(mercaptomethyl)oxetan-3-yl)methanol (2) (49.08 g, 365.70 mmol),4,5-Bis(diphenyl-phosphino)-9,9-dimethylxanthene (15.87 g, 27.43 mmol)and Tris(dibenzylideneacetone) dipalladium (16.75 g, 18.29 mmol). Themixture was stirred at 65° C. under nitrogen atmosphere for 16 hours.After completion, the mixture was filtered and the solid was washed withdichloromethane (1 L). (CAUTION! The organic phase contained only littleproduct.) Then the solid was washed with tetrahydrofuran until theproduct was little by TLC. The tetrahydrofuran phase was concentratedand the residue was beat with tetrahydrofuran/petroleum ether (200 mL/50mL) to afford the crude product7-chloro-8-(((3-(hydroxymethyl)oxetan-3-yl)methyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (4) (72.7g, crude) as a pale yellow solid.

MS (ESI) m/z 397.0 [M+H]⁺.

11-chloro-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetane]-6,8(4H,7H)-dione(5)

To a mixture of7-chloro-8-(((3-(hydroxymethyl)oxetan-3-yl)methyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(72.7 g, 183.23 mmol) and tributylphosphine (96.12 g, 366.46 mmol) intetrahydrofuran (7000 mL) was added diisopropylazodicarboxylate (74.10g, 366.46 mmol) at 0° C. under nitrogen atmosphere. The mixture wasstirred at room temperature for 18 hours. After completion, the mixturewas poured into ice-water (7000 mL) and extracted with ethyl acetate(3×7000 mL). The organic phase was concentrated and the residue waspurified by silica column (with 0.2%-1% methanol in dichloromethane) toafford the crude product11-chloro-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetane]-6,8(4H,7H)-dione (5) (34.10 g, yield:49%) as apale yellow solid.

MS (ESI) m/z 376.9 [M−H]⁻.

(2R,5S)-tert-butyl4-(11-chloro-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-8-yl)-2,5-dimethylpiperazine-1-carboxylate(6)

To a mixture of11-chloro-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetane]-6,8(4H,7H)-dione (31.00 g, 81.85 mmol) andpotassium carbonate (113.15 g, 818.68 mmol) in acetonitrile (1860 mL)and dichloromethane (930 mL) was added 2,4,6-Triisopropylbenzenesulfonylchloride (36.20 g, 119.53 mmol) at 25° C. The mixture was stirred at 25°C. for 6 hours. (2S,5R)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate(52.70 g, 245.91 mmol) was added into the reaction solution. Thereaction mixture was stirred at 25° C. for 1 hour. After completion, themixture was poured into ice-water (2000 mL) and extracted with ethylacetate (4×800 mL). The organic phase was concentrated and the residuewas purified by flash silica column (with 0.2%-1% methanol indichloromethane) to afford (2R,5S)-tert-butyl4-(11-chloro-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-8-yl)-2,5-dimethylpiperazine-1-carboxylate(6) (29.50 g, yield: 62%) as a pale-white solid.

MS (ESI) m/z 575.2 [M+H]⁺.

(2R,5S)-tert-butyl4-(11-(2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-8-yl)-2,5-dimethylpiperazine-1-carboxylate(7)

To a solution of (2R,5S)-tert-butyl4-(11-chloro-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-8-yl)-2,6-dimethylpiperazine-1-carboxylate(6) (10.4 g, 18.12 mmol) in 1,4-dioxane (90 mL) and water (15 mL) wereadded tripotassium phosphate trihydrate (14.46 g, 54.36 mmol),(2,4-difluorophenyl)boronic acid (11.45 g, 72.48 mmol), andChloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(1.41 g, 1.81 mmol). The mixture was stirred at 85° C. under nitrogenatmosphere for 3 hours. After completion, the mixture was concentratedand the residue was purified by silica gel column chromatography (with1%-3% methanol in dichloromethane) to afford (2R,5S)-tert-butyl4-(11-(2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-8-yl)-2,5-dimethylpiperazine-1-carboxylate(7) (9.9 g, yield: 84%) as a yellow solid. MS (ESI) m/z 653.1 [M+H]⁺.

11-(2,4-difluorophenyl)-8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-6(4H)-one

To a cooled mixture of (2R,5S)-tert-butyl4-(11-(2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-8-yl)-2,5-dimethylpiperazine-1-carboxylate(7) (9.9 g, 15.18 mmol) in dichloromethane (50 mL) was addedtrifluoroacetic acid (25 mL) at 0° C. The reaction solution was stirredat room temperature for 1 hour. After completion, the mixture wasconcentrated. The residue was redissolved in dichloromethane and washedwith saturated NaHCO₃. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel columnchromatography (with 7% methanol in dichloromethane) to afford11-(2,4-difluorophenyl)-8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-6(4H)-one(8.1 g, yield: 96%) as a yellow solid. MS (ESI) m/z 552.3 [M+H]+.

8-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-11-(2,4-difluorophenyl)-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-6(4H)-one(8)

To a mixture of11-(2,4-difluorophenyl)-8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-6(4H)-one(8.1 g, 14.67 mmol) and triethyl amine (2.96 g, 29.34 mmol) indichloromethane (70 mL) was added acrylic anhydride (2.77 g, 22 mmol) at0° C. The mixture was stirred at 0° C. for 1 hour. After completion, themixture was poured into ice-water (200 mL) and extracted with ethylacetate (3×200 mL). The organic phase was concentrated and the residuewas purified by silica gel column chromatography (with 2% methanol indichloromethane) to afford8-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-11-(2,4-difluorophenyl)-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-6(4H)-one(8) (6.9 g, yield: 78%) as a pale-yellow solid. MS (ESI) m/z 607.0[M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 8.87-8.70 (m, 1H), 7.22-7.11 (m, 1H),7.05-6.91 (m, 2H), 6.67-6.48 (m, 1H), 6.43-6.32 (m, 1H), 5.82-5.74 (m,1H), 5.20-4.88 (m, 5.5H), 4.44-4.26 (m, 3H), 4.00-3.64 (m, 3H),3.50-3.31 (m, 2.5H), 1.45-1.24 (m, 6H).

The above racemate (15.4 g) was dissolved in EtOH (150 mL) and separatedby chiral supercritical fluid chromatography (separation condition:Column: Chiralpak AD-H 5 μm 20×250 mm; Mobile Phase: CO₂:IPA=70:30 at 25mL/min; Temp: 25° C.; Wavelength: 254 nm) to afford the firstatropisomer P1 (6.8 g, 44% yield, 99.38% de) and the second atropisomerP2 (6.5 g, 42% yield, 98.52% de); Chiral HPLC Analytical: on CHIRALPAK®AD-H was using 5 μm 4.6×250 mm column, Mobile Phase: CO₂:IPA=70:30 at2.5 mL/min; Temp: 25° C.; Wavelength: 254 nm).

The First Atropisomer P1:

¹H NMR (400 MHz, CDCl₃) δ 8.83 (s, 1H), 7.19-7.11 (m, 1H), 7.04-6.92 (m,2H), 6.67-6.49 (m, 1H), 6.43-6.32 (m, 1H), 5.81-5.74 (m, 1H), 5.10-4.69(m, 5H), 4.41-4.28 (m, 3H), 4.18-4.03 (m, 0.5H), 3.93-3.65 (m, 3H),3.48-3.36 (m, 2.5H), 1.42-1.28 (m, 6H); Chiral SFC fraction 1:e.e.=99.38%, Rt=4.07 min.

The Second Atropisomer P2:

¹H NMR (400 MHz, CDCl₃) δ 7.84 (s, 1H), 7.21-7.13 (m, 1H), 7.05-6.92 (m,2H), 6.67-6.49 (m, 1H), 6.44-6.32 (m, 1H), 5.82-5.73 (m, 1H), 5.13-4.64(m, 5H), 4.45-4.28 (m, 3H), 4.23-4.11 (m, 0.5H), 4.01-3.87 (m, 1H),3.83-3.64 (m, 2H), 3.51-3.32 (m, 2.5H), 1.45-1.30 (m, 6H); Chiral SFCfraction 1: e.e.=98.52%, Rt=4.39 min.

Example 1120 and 1121(S)-8′-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-11′-(5-chloro-2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one(P1) and(R)-8′-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-11′-(5-chloro-2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one(P2)

((2R,5S)-tert-butyl4-(11-(5-chloro-2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-8-yl)-2,5-dimethylpiperazine-1-carboxylate(2)

To a solution of (2S,5R)-tert-butyl4-(11-chloro-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-8-yl)-2,5-dimethylpiperazine-1-carboxylate(26.00 g, 45.21 mmol) in 1,4-dioxane (550 mL) and water (130 mL) wereadded tripotassium phosphate trihydrate (28.80 g, 135.68 mmol),(5-chloro-2,4-difluorophenyl) boronic acid (18.40 g, 95.65 mmol), andChloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(7.03 g, 9.04 mmol). The mixture was stirred at 85° C. under nitrogenatmosphere for 3 hours. After completion, the mixture was concentratedand the residue was purified by silica gel column chromatography (with1%-3% methanol in dichloromethane) to afford (2R,5S)-tert-butyl4-(11-(5-chloro-2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-8-yl)-2,5-dimethylpiperazine-1-carboxylate(2) (33.00 g, crude) as a yellow solid. MS (ESI) m/z 687.6 [M+H]⁺.

11-(5-chloro-2,4-difluorophenyl)-8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-6(4H)-one(3)

To a cooled mixture of (2R,5S)-tert-butyl4-(11-(5-chloro-2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-8-yl)-2,5-dimethylpiperazine-1-carboxylate(2) (33.00 g, 45.21 mmol) in dichloromethane (60 mL) was addedtrifluoroacetic acid (30 mL) at 0° C. The reaction solution was stirredat room temperature for 1 hour. After completion, the mixture wasconcentrated. The residue was redissolved in dichloromethane and washedwith saturated NaHCO₃. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel columnchromatography (with 7% methanol in dichloromethane) and removedpalladium with Sulfhydryl-silica-gel to afford11-(5-chloro-2,4-difluorophenyl)-8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-6(4H)-one(3) (31.4 g, crude) as a yellow solid. MS (ESI) m/z 587.1 [M+H]⁺.

8-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-6(4H)-one(4)

To a mixture of11-(5-chloro-2,4-difluorophenyl)-8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-6(4H)-one(3) (31.40 g, 45.21 mmol) and triethyl amine (18.00 g, 177.88 mmol) indichloromethane (900 mL) was added acrylic anhydride (7.00 g, 55.51mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. Aftercompletion, the mixture was poured into ice-water (200 mL) and extractedwith dichloromethane (3×500 mL). The organic phase was concentrated andthe residue was purified by silica gel column chromatography (with 2%methanol in dichloromethane) to afford8-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-6(4H)-one(4) (21.10 g, yield: 72.8%) as a pale-yellow solid. MS (ESI) m/z 641.1[M+H]⁺.

The above racemate (21.1 g) was dissolved in EtOH (150 mL) and separatedby chiral supercritical fluid chromatography (separation condition:Column: Chiralpak AS-H 2 μm 20×250 cm; Mobile Phase: CO₂:EtOH (0.1DEA)=70:30 at 25 mL/min; Temp: 25° C.; Wavelength: 254 nm) to afford thetitle compounds P1 (9.69 g, 46% yield, 98.62% de) and P2 (8.04 g, 41%yield, 99.46% de);

Chiral HPLC Analytical: on CHIRALPAK® AD-H was using 2 μm 0.46×15 cmcolumn, Mobile Phase: CO₂ EtOH (0.1 DEA)=70:30 at 2.5 mL/min; Temp: 25°C.; Wavelength: 254 nm).

P1:

¹H NMR (400 MHz, CDCl₃) δ 7.83 (s, 1H), 7.26-7.21 (m, 1H), 7.06 (t,J=8.8 Hz, 1H), 6.61-6.50 (m, 1H), 6.41-6.34 (m, 1H), 5.80-5.76 (m, 1H),5.75-4.50 (m, 6H), 4.38-4.35 (m, 3H), 4.17-3.67 (m, 3H), 3.44-3.40 (m,2H), 1.39-1.25 (m, 6H);

Chiral SFC fraction 1: e.e.=98.62%, Rt=3.22 min.

P2:

¹H NMR (400 MHz, CDCl₃) 7.84 (s, 1H), 7.29-7.26 (m, 1H), 7.08 (t, J=8.8Hz, 1H), 6.63-6.51 (m, 1H), 6.42-6.38 (m, 1H), 5.80-5.76 (m, 1H),5.75-4.50 (m, 6H), 4.42-4.36 (m, 3H), 4.17-3.67 (m, 3H), 3.49-3.39 (m,2H), 1.40-1.34 (m, 6H);

Chiral SFC fraction 2: e.e.=99.46%, Rt=3.43 min.

Example 1134 (2S,6R)-tert-butyl4-((S)-11-(4-fluorophenyl)-3-morpholino-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

(R)-1-((tert-butyldiphenylsilyl)oxy)-3-chloropropan-2-ol (2)

To a mixture of (R)-3-chloropropane-1,2-diol (17 g, 153.8 mmol) andpotassium t-butoxide (34.4 g, 307.6 mmol) in dimethylformide (400 mL)was added triphenylmethanethiol (46.8 g, 169.2 mmol). The mixture wasstirred at room temperature for 18 hours. After completion, the mixturewas concentrated under reduced pressure. The crude product was pouredinto water (300 mL), extracted with ethyl acetate (3×200 mL). Thecombined organic phase was washed with brine (300 mL) and dried overanhydrous sodium sulfate. After filtration and concentration, theresidue was purified by silica gel column withdichloromethane/methanol=3/1 to afford(R)-1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-ol (2) (34g, 63% yield) as a yellow oil. MS (ESI) m/z 373.2 [M+Na]⁺.

(R)-1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-ol (3)

To a mixture of(S)-1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-ol (34 g,97.0 mmol) and imidazole (13.2 g, 194.0 mmol) in dichloromethane (270mL) was added tert-butylchlorodiphenylsilane (24 mL, 92.2 mmol) at 0° C.The mixture was stirred at room temperature for 18 hours. Aftercompletion, the mixture was concentrated under reduced pressure and theresidue was purified by silica gel column with petroleum ether/ethylacetate=20/1 to afford(R)-1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-ol (3) (36.3g, 64% yield) as a colorless oil. MS (ESI) m/z 611.3 [M+Na]⁺.

(S)-(2-azido-3-(tritylthio)propoxy)(tert-butyl)diphenylsilane (4)

To a mixture of(R)-1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-ol (3) (36.3g, 61.73 mmol) and triphenylphosphine (32.35 g, 123.46 mmol) intetrahydrofuran (200 mL) was added diethyl azodicarboxylate (21.48 g,123.46 mmol) at 0° C. under nitrogen atmosphere. The mixture was warmedto room temperature, then was added diphenyl azidophosphate (20.37 g,74.08 mmol) slowly and stirred at room temperature for 18 hours. Aftercompletion, the mixture was concentrated under reduced pressure and theresidue was purified by silica gel column with petroleum ether/ethylacetate=100/1 to afford to afford(S)-(2-azido-3-(tritylthio)propoxy)(tert-butyl)diphenylsilane (4) (31.5g, 84% yield) as a colorless oil. MS (ESI): m/z 636.4 [M+Na]⁺.

(S)-1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-amine (5)

To a solution of(S)-(2-azido-3-(tritylthio)propoxy)(tert-butyl)diphenylsilane (4) (31.5g, 51.6 mmol) in tetrahydrofuran (230 mL) and water (25 mL) were addedtriphenylphosphine (27 g, 103.2 mmol). The mixture was stirred at 70° C.for 5 hours. After completion, the mixture was concentrated underreduced pressure and the residue was purified by silica gel column withpetroleum ether/ethyl acetate (contained 2% methanol)=10/1 to afford toafford (S)-1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-amine(5) (9.3 g, 31% yield) as a colorless oil. MS (ESI): m/z 588.4 [M+Na]⁺.

(S)-benzyl(1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-yl)carbamate(6)

To a mixture of(S)-1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-amine (5)(9.0 g, 15.33 mmol) and sodium carbonate (4.87 g, 45.99 mmol) intetrahydrofuran (45 mL) and water (45 mL) was added benzylcarbonochloridate (3.14 g, 18.39 mmol). The mixture was stirred at roomtemperature for 18 hours. After completion, the mixture was poured intoice-water (300 mL) and extracted with ethyl acetate (3×150 mL). Afterconcentration, the residue was purified by silica gel column withpetroleum ether/ethyl acetate=10/1 to afford to afford (S)-benzyl(1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-yl)carbamate(6) (10.5 g, 95% yield) as a colorless oil. ¹H NMR (400 MHz, DMSO-d6) δ7.51-7.18 (m, 30H), 5.04-4.96 (m, 2H), 3.73-3.68 (m, 1H), 3.45-3.41 (m,1H), 3.29-3.25 (m, 1H), 2.44-2.40 (m, 1H), 2.33-2.27 (m, 1H), 0.88 (s,9H).

(S)-benzyl(1-((tert-butyldiphenylsilyl)oxy)-3-mercaptopropan-2-yl)carbamate (7)

To a mixture of (S)-benzyl(1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-yl)carbamate(6) (10.5 g, 14.56 mmol) and triethylsilane (3.88 g, 33.49 mmol) indichloromethane (110 mL) was added trifluoroacetic acid (11 mL, 147.84mmol). The mixture was stirred at room temperature for 4 hours. Aftercompletion, the mixture was concentrated and adjusted pH=7˜8 at 0° C.After concentration, the residue was purified by silica gel column withpetroleum ether/ethyl acetate=10/1 to afford to afford (S)-benzyl(1-((tert-butyldiphenylsilyl)oxy)-3-mercaptopropan-2-yl)carbamate (7)(4.32 g, 61% yield) as a colorless oil. MS (ESI): m/z 502 [M+Na]⁺.

(S)-benzyl(1-((tert-butyldiphenylsilyl)oxy)-3-((7-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)propan-2-yl)carbamate(8)

To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4-diol(1.95 g, 5.0 mmol) in 1,4-dioxane (50 mL), potassium carbonate (2.07 g,15.0 mmol), (S)-benzyl(1-((tert-butyldiphenylsilyl)oxy)-3-mercaptopropan-2-yl)carbamate (7)(4.32 g, 9.0 mmol), 4,5-Bis(diphenyl-phosphino)-9,9-dimethylxanthene(434 mg, 0.75 mmol) and Tris(dibenzylideneacetone) dipalladium (458 g,0.5 mmol) were added. The mixture was stirred at 60° C. under nitrogenatmosphere for 18 hours. After completion, the mixture was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography (dichloromethane/methanol=30/1) to afford (S)-benzyl(1-((tert-butyldiphenylsilyl)oxy)-3-((7-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)propan-2-yl)carbamate(8) (2.42 g, yield: 65%) as pale yellow solid. MS (ESI) m/z 743 [M+H]⁺.

(S)-benzyl(1-((7-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)-3-hydroxypropan-2-yl)carbamate(9)

To a solution of (S)-benzyl(1-((tert-butyldiphenylsilyl)oxy)-3-((7-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)propan-2-yl)carbamate(8) (2.42 g, 3.26 mmol) in Tetrahydrofuran (36 mL) was addedTetrabutylammonium fluoride (4.9 mL, 4.9 mmol) at room temperature andstirred at room temperature for 18 hours. After completion, the mixturewas extracted with ethyl acetate (3×60 mL). The combined organic phasewas washed with brine (60 mL) and dried over anhydrous sodium sulfate.After filtration and concentration, the residue was purified by silicagel column with dichloromethane/methanol=20/1 to afford (S)-benzyl(1-((7-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)-3-hydroxypropan-2-yl)carbamate(9) (780 mg, 47% yield) as a yellow solid. MS (ESI) m/z 504 [M+H]⁺.

(S)-benzyl(11-chloro-8-hydroxy-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)carbamate(10)

To a mixture of (S)-benzyl(1-((7-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)-3-hydroxypropan-2-yl)carbamate(9) (2.87 g, 5.7 mmol) and triphenylphosphoranylidene (5.97 g, 22.8mmol) in tetrahydrofuran (840 mL) was added Diethyl azodicarboxylate(3.97 g, 22.8 mmol) at 0° C. The mixture was stirred at 0° C. for 45min. After completion, the mixture was poured into ice-water (200 mL)and extracted with ethyl acetate (3×200 mL). Concentrated and theresidue was purified by C18 with 30-95% acetonitrile in water to afford(S)-benzyl(11-chloro-8-hydroxy-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)carbamate(10) (1.35 g, yield: 49%) as a white solid. MS (ESI) m/z 486.1 [M+H]⁺.

(2S,6R)-tert-butyl4-((S)-3-(((benzyloxy)carbonyl)amino)-11-chloro-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(11)

To a mixture of (S)-benzyl(11-chloro-8-hydroxy-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)carbamate(10) (1.35 g, 2.78 mmol) and potassium carbonate (3.83 g, 27.8 mmol) inacetonitrile (50 mL) was added 4-methylbenzenesulfonic anhydride (2.27g, 6.95 mmol) at 0° C. The mixture was stirred at room temperature for 4hours. After completion, (2S,6R)-tert-butyl2,6-dimethylpiperazine-1-carboxylate (2.38 g, 11.12 mmol) was added intothe reaction solution. The reaction mixture was stirred at 0° C. for 1hour. After completion, the mixture was poured into ice-water (200 mL)and extracted with ethyl acetate (3×100 mL). Concentrated and theresidue was purified by C18 column with 20-95% acetonitrile in water toafford (2S,6R)-tert-butyl4-((S)-3-(((benzyloxy)carbonyl)amino)-11-chloro-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(11) (1.15 g, yield: 60%) as a pale yellow solid. MS (ESI) m/z 683.3[M+H]⁺.

(2S,6R)-tert-butyl4-((S)-3-(((benzyloxy)carbonyl)amino)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(12)

To a solution of (2S,6R)-tert-butyl4-((S)-3-(((benzyloxy)carbonyl)amino)-11-chloro-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(11) (250 mg, 0.37 mmol) in 1,4-dioxane (10 mL) and water (2 mL),tripotassium phosphate (290 mg, 1.11 mmol), (4-fluorophenyl)boronic acid(292 mg, 1.85 mmol), and Chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(29 mg, 0.04 mmol) were added. The mixture was stirred at 80° C. undernitrogen atmosphere for 1 hour. After completion, the mixture wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography (dichloromethane/methanol=20/1) to afford(2S,6R)-tert-butyl4-((S)-3-(((benzyloxy)carbonyl)amino)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(12) (160 mg, yield: 58%) as a yellow solid. MS (ESI) m/z 742.3 [M+H]⁺.

(2S,6R)-tert-butyl4-((S)-3-amino-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(13)

To a solution of (2S,6R)-tert-butyl4-((S)-3-(((benzyloxy)carbonyl)amino)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(12) (160 mg, 0.21 mmol) in methanol (10 mL) was added Pd/C (80 mg, 50%w/w) at room temperature. The mixture was stirred at room temperaturefor 1 hour. After completion, the mixture was filtered and concentratedto afford (2S,6R)-tert-butyl4-((S)-3-amino-1-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(13) (130 mg, crude) as a yellow solid. MS (ESI) m/z 608.3 [M+H]⁺.

(2S,6R)-tert-butyl4-((S)-11-(4-fluorophenyl)-3-morpholino-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(14)

To a mixture of (2S,6R)-tert-butyl4-((S)-3-amino-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(13) (130 mg, crude) in acetonitrile (3 mL) was added Potassiumcarbonate (91 mg, 0.66 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (102mg, 0.44 mmol) at room temperature. The reaction solution was stirred at90° C. under nitrogen atmosphere for 18 hours. After completion, themixture was extracted with ethyl acetate (3×30 mL). The combined organicphase was washed with brine (30 mL) and dried over anhydrous sodiumsulfate, which was filtered and concentrated to afford(2S,6R)-tert-butyl4-((S)-11-(4-fluorophenyl)-3-morpholino-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(14) (220 mg, crude). MS (ESI) m/z 678.3 [M+H]⁺.

(2S,6R)-tert-butyl4-((S)-11-(4-fluorophenyl)-3-morpholino-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(15)

To a cooled mixture of (2S,6R)-tert-butyl4-((S)-11-(4-fluorophenyl)-3-morpholino-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(14) (220 mg, crude) in dichloromethane (5 mL) was added trifluoroaceticacid (1.5 mL) at 0° C. The reaction solution was stirred at roomtemperature for 1 hour. After completion, the mixture was concentrated.The residue was redissolved in dichloromethane and washed with saturatedNaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel column chromatography(dichloromethane/methanol=15/1) to afford (2S,6R)-tert-butyl4-((S)-11-(4-fluorophenyl)-3-morpholino-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(15) (49 mg, three steps yield: 38%) as a yellow solid. MS (ESI) m/z578.3 [M+H]⁺.

(2S,6R)-tert-butyl4-((S)-11-(4-fluorophenyl)-3-morpholino-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(16)

To a mixture of (2S,6R)-tert-butyl4-((S)-11-(4-fluorophenyl)-3-morpholino-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(15) (47.0 mg, 0.08 mmol) and triethyl amine (24 mg, 0.24 mmol) indichloromethane (5 ml) was added acrylic anhydride (15 mg, 0.12 mmol) at0° C. The mixture was stirred at 0° C. for 1 h. After completion, themixture was poured into ice-water (30 mL) and extracted withdichloromethane (3×30 mL). After concentration, the residue was purifiedby preparative High Performance Liquid Chromatography (20% to 95%acetonitrile in water) to afford (2S,6R)-tert-butyl4-((S)-11-(4-fluorophenyl)-3-morpholino-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(16) (14.0 mg, yield:28%) as a white solid. MS (ESI) m/z 632.3 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.21-7.15 (m, 4H), 6.66-6.59 (m,1H), 6.42 (dd, J=2.0 Hz, 16.4 Hz, 1H), 5.78 (dd, J=1.6 Hz, 10.4 Hz, 1H),4.75-4.72 (m, 3H), 4.15 (t, J=10.8 Hz, 2H), 3.72-3.66 (m, 4H), 3.37-3.08(m, 5H), 2.70-2.64 (m, 4H), 1.57-1.49 (m, 6H), 1.31-1.25 (m, 1H).

TABLE 8 Examples 1100 to 1140 % CAF 10 uM Ex. MS @ # Name Structure ¹HNMR (M + H)⁺ 60 min 1100 8′-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11′-(5-chloro- 2,4-difluorophenyl)- 10′- (trifluoromethyl)-2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino [2,3,4-ij]quinazolin]-6′-one

¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.26-7.22 (m, 1H), 7.06 (t, J =8.4 Hz, 1H), 6.62 (dd, J = 16.8 Hz, 10.8 Hz, 1H), 6.41 (dd, J = 16.4 Hz,1.6 Hz, 1H), 5.78 (dd, J = 10.4 Hz, 2.0 Hz, 1H), 5.25-4.52 (m, 6H), 4.35(dd, J = 6.4 Hz, 2.0 Hz, 2H), 4.18-4.10 (m, 2H), 3.47-3.42 (m, 2H),3.41-3.33 (m, 2H), 1.56-1.49 (m, 6H). 641.2 88.8 1101 (3S,10R)-7-((2S,5R)-4-acryloyl- 2,5- dimethylpiperazin- 1-yl)-3- (methoxymethyl)-10-(1-methyl-1H- indazol-7-yl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H), 7.91-7.85 (m, 2H), 7.25-7.21 (m,1H), 7.14 (d, J = 6.8 Hz, 1H), 6.67- 6.51 (m, 1H), 6.38 (t, J = 14.8 Hz,1H), 5.78 (t, J = 8.0 Hz, 1H), 5.45-5.41 (m, 1H), 5.10-5.05 (m, 0.5H),4.85- 4.71 (m, 1H), 4.47-4.44 (m, 0.5H), 4.37-4.34 (m, 1H), 4.10-4.06(m, 0.5H), 3.81- 3.64 (m, 4H), 3.56-3.54 (m, 3H), 3.37-3.24 (m, 4.5H),3.00-2.97 (m, 1H), 1.48-1.42 (m, 6H). 613.2 0 1102 (3S,10S)-7-((2S,5R)-4-acryloyl- 2,5- dimethylpiperazin- 1-yl)-3- (methoxymethyl)-10-(1-methyl-1H- indazol-7-yl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.94 (d, J = 15.6 Hz, 1H), 7.87(d, J = 8.0 Hz, 1H), 7.27-7.23 (m, 1H), 7.13 (d, J = 7.2 Hz, 1H),6.68-6.51 (m, 1H), 6.38 (t, J = 14.8 Hz, 1H), 5.78 (t, J = 8.8 Hz, 1H),5.39-5.36 (m, 1H), 5.12-5.09 (m, 0.5H), 4.81-4.68 (m, 1H), 4.55-4.44 (m,1H), 4.39-4.36 (m, 0.5H), 4.21-4.18 (m, 0.5H), 3.72-3.56 (m, 7H), 3.35(s, 3H), 3.28-3.19 (m, 1.5H), 3.03-2.99 (m, 1H), 1.55-1.46 (m, 6H).613.2 94.5 1103 (S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(4- fluorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.23-7.15 (m, 4H), 6.66-6.59 (m,1H), 6.40 (dd, J = 2.0 Hz, 16.8 Hz, 1H), 5.77 (dd, J = 2.0 Hz, 10.8 Hz,1H), 5.44-5.43 (m, 1H), 4.76-4.57 (m, 2H), 4.21-4.16 (m, 2H), 3.70-3.62(m, 2H), 3.40-3.30 (m, 6H), 2.98-2.94 (m, 1H), 1.62 (d, J = 7.2 Hz, 3H),1.47 (d, J = 7.2 Hz, 3H). 577.3 98 1104 8-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-11-(2,4- difluorophenyl)-1′- ethyl-10-(trifluoromethyl)- 2H- spiro[[1,4] thiazepino[2,3,4-ij]quinazoline-3,3′- azetidin]-6(4H)-one

¹H NMR (400 MHz, CDCl₃) δ 8.11 (s, 1H), 7.21-7.15 (m, 1H), 7.09-6.96 (m,2H), 6.71-6.62 (m, 1H), 6.48-6.42 (m, 1H), 5.82 (dd, J = 14.0 Hz, 2.4Hz, 1H), 4.70-4.65 (m, 4H), 4.21-4.18 (m, 2H), 3.55-3.31(m, 8H),2.67-2.61 (m, 2H), 1.58-1.50 (m, 6H), 1.05 (t, J = 7.2 Hz, 3H). 634.397.2 1105 (3R)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro- 2,4-difluorophenyl)- 3-morpholino-10-(trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin- 6-one

¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.33-7.29 (m, 1H), 7.13-7.07 (m,1H), 6.72-6.63 (m, 1H), 6.49-6.43 (m, 1H), 5.83 (dd, J = 14.0 Hz, 2.8Hz, 1H), 4.79- 4.69 (m, 4H), 4.22-4.17 (m, 2H), 3.83-3.70 (m, 4H),3.42-3.19 (m, 5H), 2.72-2.65 (m, 4H), 1.61-1.57 (m, 6H). 684.2 95.6 1106(S)-7-(4- acryloylpiperazin-1- yl)-10-(4- fluorophenyl)-3-(methoxymethyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (300 MHz, CDCl₃) δ 7.85 (s, 1H), 7.26- 7.19 (m, 4H), 6.69-6.60(m, 1H), 6.41 (d, J = 21.0 Hz, 1H), 5.83 (d, J = 12.0 Hz, 1H), 5.48-5.44(m, 1H), 4.07-3.96 (m, 3H), 3.91-3.76 (m, 5H), 3.73-3.70 (m, 2H), 3.45(s, 3H), 3.37 (d, J = 15.0 Hz, 1H), 3.00 (d, J = 15.0 Hz, 1H). 549.298.2 1107 (3S,10R)-7-(4- acryloylpiperazin-1- yl)-10-(5-chloro-2,4-difluorophenyl)- 3-(methoxymethyl)- 9-(trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.29- 7.27 (m, 1H), 7.09-7.05(m, 1H), 6.62-6.55 (m, 1H), 6.39-6.34 (m, 1H), 5.79 (dd, J = 10.4 Hz,2.0 Hz, 1H), 5.45-5.40 (m, 1H), 3.97-3.88 (m, 3H), 3.80-3.78 (m, 5H),3.66 (d, J = 7.2 Hz, 2H), 3.42-3.36 (m, 4H), 3.03 (dd, J = 13.6 Hz, 2.8Hz, 1H). 601.1 97 1108 (3S,10S)-7-(4- acryloylpiperazin-1-yl)-10-(5-chloro- 2,4-difluorophenyl)- 3-(methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.28- 7.26 (m, 1H), 7.07 (t, J =8.8 Hz, 1H), 6.62-6.55 (m, 1H), 6.39-6.35 (m, 1H), 5.79 (dd, J = 10.4Hz, 1.6 Hz, 1H), 5.47-5.43 (m, 1H), 4.00-3.90 (m, 3H), 3.80-3.73 (m,5H), 3.67-3.61 (m, 2H), 3.39-3.35 (m, 4H), 3.02 (dd, J = 13.6 Hz, 2.8Hz, 1H). 601.1 85 1109 (S)-8′-((2S,5R)-4- acryloyl-2,5-dimethylpiperazin- 1-yl)-11′-(2,4- difluorophenyl)-10′-(trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]- 6′-one

¹H NMR (400 MHz, CDCl₃) δ 8.83 (s, 1H), 7.19- 7.11 (m, 1H), 7.04-6.92(m, 2H), 6.67-6.49 (m, 1H), 6.43-6.32 (m, 1H), 5.81-5.74 (m, 1H),5.10-4.69 (m, 5H), 4.41-4.28 (m, 3H), 4.18-4.03 (m, 0.5H), 3.93-3.65 (m,3H), 3.48-3.36 (m, 2.5H), 1.42-1.28 (m, 6H). 607.3 93 1110(R)-8′-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin- 1-yl)-11′-(2,4-difluorophenyl)-10′- (trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′-[1,4]thiazepino [2,3,4-ij]quinazolin]- 6′-one

¹H NMR (400 MHz, CDCl₃) δ 7.84 (s, 1H), 7.21-7.13 (m, 1H), 7.05-6.92 (m,2H), 6.67-6.49 (m, 1H), 6.44-6.32 (m, 1H), 5.82-5.73 (m, 1H), 5.13-4.64(m, 5H), 4.45-4.28 (m, 3H), 4.23-4.11 (m, 0.5H), 4.01-3.87 (m, 1H),3.83-3.64 (m, 2H), 3.51-3.32 (m, 2.5H), 1.45-1.30 (m, 6H). 607.3 96.11111 8′-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin- 1-yl)-11′-(4-fluorophenyl)-10′- (trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′-[1,4]thiazepino [2,3,4-ij]quinazolin]- 6′-one

¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 1H), 7.26-7.15 (m, 4H), 6.63-6.51 (m,1H), 6.38 (t, J = 15.2 Hz, 1H), 5.80- 5.76 (m, 1H), 5.01-4.70 (m, 5H),4.41-4.30 (m, 4H), 3.91-3.67 (m, 3H), 3.42-3.33 (m, 2H), 1.39-1.25 (m,6H). 589.3 95.4 1112 (R)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(4- fluorophenyl)-3- morpholino-10- (trifluoromethyl)-3,4-dihydro-2H,6H- [1,4]thiazepino [2,3,4-ij]quinazolin- 6-one

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.24- 7.15 (m, 4H), 6.66-6.59(m, 1H), 6.41 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.77 (dd, J = 10.4 Hz, 2.0Hz, 1H), 4.75- 4.64 (m, 4H), 4.18-4.16 (m, 2H), 3.70-3.67 (m, 4H),3.37-3.09 (m, 5H), 2.66-2.60 (m, 4H), 1.57-1.54 (m, 6H). 632.4 92.4 1113(3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-9-chloro-10-(2,4- difluorophenyl)-3- (methoxymethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one

¹H NMR (400 MHz, MeOH-d₄) δ 7.90 (s, 1H), 7.42-7.26 (m, 1H), 7.22- 7.10(m, 2H), 6.83 (dd, J = 16.7, 10.6 Hz, 1H), 6.28 (dd, J = 16.7, 2.0 Hz,1H), 5.41-5.31 (m, 1H), 4.80- 4.52 (m, 2H), 4.44-4.31 (m, 1H), 4.25 (d,J = 13.5 Hz, 1H), 3.79-3.64 (m, 1H), 3.63-3.50 (m, 2H), 3.49- 3.41 (m,2H), 3.39 (s, 3H), 3.38-3.33 (m, 1H), 3.15 (td, J = 13.2, 3.0 Hz, 1H),1.54 (dd, J = 7.0, 2.6 Hz, 3H), 1.40 (dd, J = 7.0, 3.2 Hz, 3H); 561.296.8 1114 (3R,11R)-8- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro- 2,4-difluorophenyl)- 3-morpholino-10-(trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin- 6-one

¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.28- 7.24 (m, 1H), 7.05 (t, J =8.8 Hz, 1H), 6.66-6.59 (m, 1H), 6.43-6.39 (m, 1H), 5.78 (dd, J = 10.4Hz, 1.6 Hz, 1H), 4.76-4.62 (m, 4H), 4.17-4.14 (m, 2H), 3.81-3.66 (m,4H), 3.38-3.17 (m, 5H), 2.77-2.58 (m, 4H), 1.58-1.54 (m, 6H). 684.3 71.71115 (3R,11S)-8- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro- 2,4-difluorophenyl)- 3-morpholino-10-(trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin- 6-one

¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.26- 7.24 (m, 1H), 7.06 (t, J =8.8 Hz, 1H), 6.66-6.59 (m, 1H), 6.43-6.39 (m, 1H), 5.78 (dd, J = 10.4Hz, 2.0 Hz, 1H), 4.74-4.64 (m, 3H), 4.19-4.13 (m, 3H), 3.78-3.65 (m,4H), 3.38-3.18 (m, 5H), 2.73-2.63 (m, 4H), 1.57-1.53 (m, 6H). 684.3 42.51116 8′-(4- acryloylpiperazin-1- yl)-11′-(4- fluorophenyl)-10′-(trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]- 6′-one

¹H NMR 561.0 98.4 1117 8′-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11′-(4- fluorophenyl)-10′- (trifluoromethyl)- 2′H,4′H,6′H-spiro[oxetane-3,3′- [1,4]thiazepino [2,3,4-ij]quinazolin]- 6′-one

¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.22- 7.15 (m, 4H), 6.66-6.59(m, 1H), 6.43-6.39 (m, 1H), 5.78 (dd, J = 10.4 Hz, 1.6 Hz, 1H),4.79-4.60 (m, 6H), 4.34 (d, J = 6.8 Hz, 2H), 4.17- 4.14 (m, 2H),3.39-3.35 (m, 4H), 1.57-1.54 (m, 6H). 589.4 96.9 1118 (R)-8-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin- 1-yl)-11-(4- fluorophenyl)-3-(pyrrolidin-1-yl)-10- (trifluoromethyl)- 3,4-dihydro-2H,6H-[1,4]thiazepino [2,3,4-ij]quinazolin- 6-one

¹H NMR (400 MHz, CDCl₃) δ 8.04 (s, 1H), 7.24-7.13 (m, 4H), 6.60-6.59 (m,1H), 6.43-6.38 (m, 1H), 5.77 (dd, J = 10.4 Hz, 1.6 Hz, 1H), 4.83-4.61(m, 4H), 4.18-4.14 (m, 2H), 3.36-3.09 (m, 5H), 2.78-2.65 (m, 4H),1.84-1.81 (m, 4H), 1.55-1.47 (m, 6H). 616.2 95.7 1119 (3S,10S)-7-(4-acryloylpiperazin- 1-yl)-3- (methoxymethyl)- 10-(1-methyl-1H-indazol-7-yl)-9- (trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H), 7.88-7.86 (m, 2H), 7.25-7.23 (m,1H), 7.15-7.13 (d, J = 7.2 Hz, 1H), 6.63-6.57 (m, 1H), 6.40-6.35 (m,1H), 5.80 (dd, J = 8.4 Hz, 2 Hz, 1H), 5.42- 5.39 (m, 1H), 4.04-4.03 (m,3H), 3.79-3.75 (m, 5H), 3.69-3.66 (m, 1H), 3.61-3.57 (m, 4H), 3.35 (s,3H), 3.28 (dd, J = 13.2 Hz, J = 2.8 Hz, 1H), 3.00 (dd, J = 13.2 Hz, 2.4Hz, 1H). 585.6 99.4 1120 (S)-8′-((2S,5R)-4- acryloyl-2,5-dimethylpiperazin- 1-yl)-11′-(5-chloro- 2,4-difluorophenyl)- 10′-(trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]- 6′-one

¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 1H), 7.26-7.21 (m, 1H), 7.06 (t, J =8.8 Hz, 1H), 6.61-6.50 (m, 1H), 6.41-6.33 (m, 1H), 5.80-5.76 (m, 1H),5.00-4.74 (m, 5H), 4.41-4.34 (m, 3H), 4.17-3.67 (m, 3.5H), 3.43-3.40 (m,2.5H), 1.39-1.32 (m, 6H). 641.1 64.9 1121 (R)-8′-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-11′-(5-chloro-2,4-difluorophenyl)- 10′- (trifluoromethyl)- 2′H,4′H,6′H-spiro[oxetane-3,3′- [1,4]thiazepino [2,3,4-ij]quinazolin]- 6′-one

¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 1H), 7.28-7.25 (m, 1H), 7.06 (t, J =8.8 Hz, 1H), 6.65-6.50 (m, 1H), 6.41-6.33 (m, 1H), 5.80-5.76 (m, 1H),5.01-4.71 (m, 5H), 4.42-4.35 (m, 3H), 3.93-3.67 (m, 3.5H), 3.49-3.39 (m,2.5H), 1.40-1.25 (m, 6H). 641.1 95.5 1122 8′-((2S,5R)-4- acryloyl-2,5-dimethylpiperazin- 1-yl)-11′-(5-chloro- 2,4-difluorophenyl)- 10′-(trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]- 6′-one

¹H NMR (400 MHz, MeOH- d₄) δ 7.97 (s, 1H), 7.50 (dd, J = 15.3, 7.8 Hz,1H), 7.34 (td, J = 9.1, 3.3 Hz, 1H), 6.91-6.72 (m, 1H), 6.34- 6.22 (m,1H), 5.81 (ddd, J = 9.8, 7.3, 1.9 Hz, 1H), 4.88- 4.59 (m, 3H), 4.45 (d,J = 6.3 Hz, 2H), 3.99-3.71 (m, 1H), 3.71-3.46 (m, 2H), 1.43 (dd, J =16.2, 6.6 Hz, 3H); 641.2 74.3 1123 8′-(4- acryloylpiperazin-1-yl)-11′-(2,4- difluorophenyl)-10′- (trifluoromethyl)- 2′H,4′H,6′H-spiro[oxetane-3,3′- [1,4]thiazepino [2,3,4-ij]quinazolin]- 6′-one

¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 1H), 7.16 (q, J = 7.6 Hz, 1H),7.04-6.92 (m, 2H), 6.62-6.55 (m, 1H), 6.39-6.35 (m, 1H), 5.80-5.77 (m,1H), 5.15-4.55 (m, 4H), 4.35 (t, J = 6.4 Hz, 2H), 3.96-3.73 (m, 8H),3.43-3.39 (m, 2H). 579.2 95.2 1124 (R)-8′-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-11′-(5-chloro- 2,4-difluorophenyl)- 10′-(trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]- 6′-one

¹H NMR (400 MHz, MeOH- d₄) δ 8.18 (s, 1H), 7.52 (t, J = 7.5 Hz, 1H),7.37 (t, J = 9.1 Hz, 1H), 6.85 (dd, J = 16.7, 10.6 Hz, 1H), 6.31 (dd, J= 16.7, 2.0 Hz, 1H), 5.82 (dd, J = 10.6, 2.0 Hz, 1H), 4.88-4.58 (m, 4H),4.46 (dd, J = 6.4, 2.4 Hz, 2H), 4.27 (d, J = 13.5 Hz, 2H), 3.58 (d, J =6.6 Hz, 2H), 3.46 (dt, J = 13.7, 4.5 Hz, 2H), 1.59-1.46 (m, 6H). 641.196.2 1125 (S)-8′-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11′-(5-chloro- 2,4-difluorophenyl)- 10′- (trifluoromethyl)-2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino [2,3,4-ij]quinazolin]-6′-one

¹H NMR (400 MHz, MeOH- d₄) δ 8.16 (s, 1H), 7.50 (t, J = 7.7 Hz, 1H),7.34 (t, J = 9.1 Hz, 1H), 6.83 (dd, J = 16.7, 10.6 Hz, 1H), 6.29 (dd, J= 16.6, 2.0 Hz, 1H), 5.80 (dd, J = 10.6, 2.0 Hz, 1H), 4.88-4.54 (m, 4H),4.44 (dd, J = 6.4, 2.4 Hz, 2H), 4.25 (d, J = 13.5 Hz, 2H), 3.56 (d, J =6.6 Hz, 2H), 3.44 (dt, J = 13.9, 4.5 Hz, 2H), 1.55-1.41 (m, 6H) 641.192.1 1126 (3S,10S)-7- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(4-fluoro-1- methyl-1H-indazol- 7-yl)-3- (methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino [2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, MeOH- d₄) δ 8.22 (s, 1H), 8.16 (s, 1H), 7.18 (dd, J =8.0, 4.8 Hz, 1H), 6.98 (dd, J = 9.7, 7.9 Hz, 1H), 6.85 (dd, J = 16.7,10.6 Hz, 1H), 6.30 (dd, J = 16.6, 2.0 Hz, 1H), 5.81 (dd, J = 10.6, 2.0Hz, 1H), 5.41-5.31 (m, 1H), 4.84- 4.55 (m, 2H), 4.39 (d, J = 13.6 Hz,1H), 4.30 (d, J = 13.6 Hz, 1H), 3.74-3.60 (m, 3H), 3.56 (s, 3H),3.55-3.37 (m, 3H), 3.36 (s, 3H), 3.35- 3.33 (m, 1H), 3.15 (dd, J = 13.7,3.0 Hz, 1H), 1.60 (d, J = 6.9 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H) 631.346.8 1127 (R)-8′-(4- acryloylpiperazin-1- yl)-11′-(2,4-difluorophenyl)-10′- (trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′-[1,4]thiazepino [2,3,4-ij]quinazolin]- 6′-one

¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 1H), 7.16 (q, J = 7.6 Hz, 1H),7.04-6.92 (m, 2H), 6.62-6.55 (m, 1H), 6.39-6.35 (m, 1H), 5.80-5.77 (m,1H), 5.08-4.53 (m, 4H), 4.35 (t, J = 6.4 Hz, 2H), 3.97-3.74 (m, 8H),3.46-3.38 (m, 2H). 579.2 95.3 1128 (S)-8′-(4- acryloylpiperazin-1-yl)-11′-(2,4- difluorophenyl)-10′- (trifluoromethyl)- 2′H,4′H,6′H-spiro[oxetane-3,3′- [1,4]thiazepino [2,3,4-ij]quinazolin]- 6′-one

¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 1H), 7.16 (q, J = 7.6 Hz, 1H),7.04-6.92 (m, 2H), 6.62-6.55 (m, 1H), 6.39-6.35 (m, 1H), 5.80-5.77 (m,1H), 5.23-4.51 (m, 4H), 4.35 (t, J = 6.4 Hz, 2H), 3.97-3.68 (m, 8H),3.43 (s, 2H). 579.2 65.8 1129 (3R)-8-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-11-(5-chloro- 2,4-difluorophenyl)-3-(pyrrolidin-1-yl)- 10- (trifluoromethyl)- 3,4-dihydro-2H,6H-[1,4]thiazepino [2,3,4-ij]quinazolin- 6-one

¹H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H), 7.25-7.23 (m, 1H), 7.04 (t, J =16 Hz, 1H), 6.66-6.59 (m, 1H), 6.43-6.38 (m, 1H), 5.77 (dd, J = 10.4 Hz,2.0 Hz, 1H), 4.82-4.65 (m, 4H), 4.18-4.14 (m, 2H), 3.39-3.14 (m, 5H),2.79-2.66 (m, 4H), 1.87-1.76 (m, 4H), 1.58-1.46 (m, 6H). 668.2 69 1130(3S,10S)-7- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-3-(methoxymethyl)- 10-(1-methyl-1H- indazol-7-yl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino [2,3,4-ij]quinazolin- 5-one

¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 8.05 (s, 1H), 7.85 (d, J = 8.0Hz, 1H), 7.25-7.21 (m, 1H), 7.12 (d, J = 6.8 Hz, 1H), 6.66-6.60 (m, 1H),6.42 (d, J = 8.4 Hz, 1H), 5.78 (d, J = 10.4 Hz, 1H), 5.48-5.45 (m, 1H),4.85-4.56 (m, 2H), 4.20 (t, J = 12.8 Hz, 2H), 3.69-3.55 (m, 5H),3.43-3.25 (m, 6H), 2.98 (d, J = 12.4 Hz, 1H), 1.62 (d, J = 6.8 Hz, 3H),1.50 (d, J = 6.4 Hz, 3H). 613.3 95.6 1131 (3S,10R)-7- ((3S,5R)-4-acryloyl-3,5- dimethylpiperazin- 1-yl)-3- (methoxymethyl)-10-(1-methyl-1H- indazol-7-yl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino [2,3,4-ij]quinazolin- 5-one

¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 8.06 (s, 1H), 7.87 (dd, J = 0.8Hz, 8.0 Hz, 1H), 7.28-7.24 (m, 1H), 7.14 (d, J = 7.2 Hz, 1H), 6.67- 6.60(m, 1H), 6.45-6.39 (m, 1H), 5.78 (dd, J = 10.0 Hz, 2.0 Hz, 1H),5.45-5.40 (m, 1H), 4.86-4.55 (m, 2H), 4.25-4.20 (m, 2H), 3.68-3.55 (m,5H), 3.45-3.35 (m, 5H), 3.29-3.25 (m, 1H), 3.03-2.98 (m, 1H), 1.65 (d, J= 7.2 Hz, 3H), 1.48 (d, J = 6.8 Hz, 3H). 613.3 18.2 1132(S)-8′-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-11′-(1-methyl-1H-indazol-7-yl)- 10′- (trifluoromethyl)- 2′H,4′H,6′H-spiro[oxetane-3,3′- [1,4]thiazepino [2,3,4-ij]quinazolin]- 6′-one

¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 8.06 (s, 1H), 7.86 (d, J = 8.0Hz, 1H), 7.25-7.22 (m, 1H), 7.11 (d, J = 7.2 Hz, 1H), 6.62-6.60 (m, 1H),6.44-6.40 (m, 1H), 5.79 (dd, J = 10.4 Hz, 1.6 Hz, 1H), 5.34-4.47 (m,6H), 4.32-4.28 (m, 2H), 4.20-4.14 (m, 2H), 3.56 (s, 3H), 3.44- 3.38 (m,4H), 1.31-1.25 (m, 6H). 625.4 85.6 1133 (R)-8′-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-11′-(1-methyl- 1H-indazol-7-yl)- 10′-(trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]- 6′-one

¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 8.06 (s, 1H), 7.86 (dd, J = 8.4Hz, 3.2 Hz, 1H), 7.25-7.22 (m, 1H), 7.11 (d, J = 6.0 Hz, 1H), 6.68- 6.60(m, 1H), 6.44-6.40 (m, 1H), 5.79 (d, J = 9.6 Hz, 1H), 5.34-4.53 (m, 6H),4.35-4.28 (m, 2H), 4.20-4.14 (m, 2H), 3.59 (s, 3H), 3.44- 3.34 (m, 4H),1.31-1.26 (m, 6H). 625.4 54.1 1134 (S)-8-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-11-(4- fluorophenyl)-3- morpholino-10-(trifluoromethyl)- 3,4-dihydro- [1,4]thiazepino [2,3,4-ij]quinazolin-6(2H)-one

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.21-7.15 (m, 4H), 6.66-6.59 (m,1H), 6.42 (dd, J = 2.0 Hz, 16.4 Hz, 1H), 5.78 (dd, J = 1.6 Hz, 10.4 Hz,1H), 4.75-4.72 (m, 3H), 4.15 (t, J = 10.8 Hz, 2H), 3.72-3.66 (m, 4H),3.37-3.08 (m, 5H), 2.70-2.64 (m, 4H), 1.57-1.49 (m, 6H), 1.31-1.25 (m,1H). 632.4 76.8 1135 (3S,11S)-8- ((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-11-(5-chloro- 2,4-difluorophenyl)-3-morpholino-10- (trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin- 6-one

¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.27-7.23 (m, 1H), 7.05 (t, J =8.8 Hz, 1H), 6.65-6.59 (m, 1H), 6.43 (dd, J = 1.6 Hz, 16.8 Hz, 1H), 5.78(dd, J = 1.6 Hz, 10.4 Hz, 1H), 4.81-4.60 (m, 4H), 4.16 (d, J = 12.8 Hz,2H), 3.72-3.71 (m, 4H), 3.36-3.18 (m, 5H), 2.69-2.67 (m, 4H), 1.64-1.53(m, 6H). 684.3 72.7 1136 (3S,11R)-8- ((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-11-(5-chloro- 2,4-difluorophenyl)-3-morpholino-10- (trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin- 6-one

¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.27-7.23 (m, 1H), 7.05 (t, J =8.8 Hz, 1H), 6.65-6.59 (m, 1H), 6.43 (dd, J = 2.0 Hz, 16.8 Hz, 1H), 5.78(dd, J = 2.0 Hz, 10.4 Hz, 1H), 4.84-4.59 (m, 4H), 4.14 (t, J = 15.6 Hz,2H), 3.73-3.68 (m, 4H), 3.38-3.15 (m, 5H), 2.72-2.58 (m, 4H), 1.54-1.52(m, 6H). 684.3 82.7 1137 (3S,11R)-8- ((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-11-(5-chloro- 2,4-difluorophenyl)-3-(pyrrolidin-1-yl)- 10- (trifluoromethyl)- 3,4-dihydro-2H,6H-[1,4]thiazepino [2,3,4-ij]quinazolin- 6-one

¹H NMR (400 MHz, CDCl₃) δ: 8.06 (s, 1H), 7.29-7.24 (m, 1H), 7.04 (t, J =8.4 Hz, 1H), 6.66-6.59 (m, 1H), 6.44-6.38 (m, 1H), 5.78 (dd, J = 16.8Hz, 2.0 Hz, 1H), 4.81-4.51 (m, 4H), 4.17-4.13 (m, 2H), 3.35-3.30 (m,3H), 3.19-3.14 (m, 2H), 2.76-2.67 (m, 4H), 1.83-1.78 (m, 4H), 1.58-1.51(m, 6H). 668.3 83.4 1138 (3S,11S)-8- ((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-11-(5-chloro- 2,4-difluorophenyl)-3-(pyrrolidin-1-yl)- 10- (trifluoromethyl)- 3,4-dihydro-2H,6H-[1,4]thiazepino [2,3,4-ij]quinazolin- 6-one

¹H NMR (400 MHz, CDCl₃) δ: 8.17 (s, 1H), 8.08 (s, 1H), 7.90 (d, J = 8.8Hz, 1H), 7.26-7.24 (m, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.67-6.60 (m, 1H),6.44- 6,39 (m, 1H), 5.81 (d, J = 12.4 Hz, 1H), 5.47 (s, 1H), 4.27 (d, J= 13.6 Hz, 2H), 3.57-3.39 (m, 5H), 3.22- 3.07 (m, 5H), 3.01-3.96 (m,11H), 1.66 (d, J = 6.8 Hz, 3H), 1.49 (d, J = 6.8 Hz, 3H), 1.36 (t, J =7.2 Hz, 3H). 668.3 50.5 1139 (3S,10R)-7- ((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4-difluorophenyl)-3-(methoxymethyl)- 9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin- 5-one

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.28-7.24 (m, 1H), 7.07 (t, J =8.8 Hz, 1H), 6.65-6.59 (m, 1H), 6.40 (dd, J = 1.6 Hz, 16.8 Hz, 1H), 5.77(dd, J = 1.2 Hz, 10.0 Hz, 1H), 5.45-5.44 (m, 1H), 4.73-4.58 (m, 2H),4.21-4.15 (m, 2H), 3.67-3.64 (m, 2H), 3.41-3.31 (m, 6H), 3.05-3.01 (m,1H), 1.61 (m, J = 6.8 Hz, 3H), 1.47 (d, J = 6.8 Hz, 3H). 629.2 95.9 1140(3S,10S)-7- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-chloro- 2,4-difluorophenyl)- 3-(methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino [2,3,4-ij]quinazolin-5-one

¹H NMR (400 MHz, CDCl₃) δ: 8.07 (s, 1H), 7.28-7.25 (m, 1H), 7.07 (t, J =8.8 Hz, 1H), 6.65-6.59 (m, 1H), 6.40 (dd, J = 1.6 Hz, 16.4 Hz, 1H), 5.77(dd, J = 1.6 Hz, 10.4 Hz, 1H), 5.48-5.45 (m, 1H), 4.76-4.59 (m, 2H),4.21-4.16 (m, 2H), 3.68-3.59 (m, 2H), 3.39-3.30 (m, 6H), 3.04-3.00 (m,1H), 1.61-1.59 (m, 3H), 1.46 (d, J = 6.4 Hz, 3H). 629.2 93.9

Example 1001:(3R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(2,4-difluorophenyl)-3-(dimethylamino)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3R)-11-(2,4-difluorophenyl)-3-(dimethylamino)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 38% yield as a white solid. m/z (ESI,+ve)=608.2 [M+H]⁺

1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.34-7.24 (m, 1H), 7.13 (m,2H), 6.84 (dd, J=16.6, 10.6 Hz), 6.29 (dd, J=16.6, 2.0 Hz), 5.80 (dd,J=10.6, 2.0 Hz), 4.76-4.57 (m, 2H), 4.40-4.27 (m, 2H), 3.79-3.71 (m,1H), 3.65-3.58 (m, 1H), 3.53-3.41 (m, 2H), 3.21-3.10 (m, 1H), 2.64-2.48(m, 2H), 2.23 (s, 6H), 1.54-1.44 (m, 6H)

Step 1: (S)-1-(benzyloxy)-3-(tritylthio)propan-2-ol

The title compound was prepared analogously to Example 454, step 1,where (2S)-2-(benzyloxymethyl)oxirane was substituted in place of(2R)-2-(benzyloxymethyl)oxirane. The title compound was isolated in 70%yield as a colorless oil. m/z (ESI, +ve)=663.2 [M+Na]

Step 2: (S)-1-(benzyloxy)-3-(tritylthio)propan-2-yl methanesulfonate

The title compound was prepared analogously to Example 454, step 2,where (S)-1-(benzyloxy)-3-(tritylthio)propan-2-ol was substituted inplace of (R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol. The title compoundwas isolated in 52% yield as a colorless oil.

1H NMR (400 MHz, CDCl3) δ 7.45-7.42 (m, 5H), 7.34-7.24 (m, 15H),4.52-4.41 (m, 2H), 4.33 (qd, J=6.4, 4.8 Hz, 1H), 3.55-3.43 (m, 2H), 2.95(s, 3H), 2.64 (qd, J=13.4, 6.5 Hz, 2H).

Step 3: (R)-3-(benzyloxy)-2-(dimethylamino)propane-1-thiol

A solution of (S)-1-(benzyloxy)-3-(tritylthio)propan-2-ylmethanesulfonate (6 g, 11.6 mmol) in 115 mL of N,N-dimethylamine wasstirred at 70° C. overnight. The mixture was cooled to room temperatureand the volatiles were removed under reduced pressure to afford aresidue that was purified by silica gel chromatography (0-10% MeOH indichloromethane). The title compound was isolated in 9% yield as a paleyellow oil. m/z (ESI, +ve)=226.2 [M+H]⁺

Step 4:8-(((R)-3-(benzyloxy)-2-(dimethylamino)propyl)thio)-7-(2,4-difluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 where(R)-3-(benzyloxy)-2-(dimethylamino)propane-1-thiol was substituted inplace of 2-mercaptoethan-1-ol. The title compound was isolated in 65%yield as a pale yellow oil. m/z (ESI, +ve)=566.1 [M+H]⁺

Step 5:7-(2,4-difluorophenyl)-8-(((R)-2-(dimethylamino)-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

A 1M solution of Boron tribromide in dichloromethane (0.32 mL) was addedover a solution of8-(((R)-3-(benzyloxy)-2-(dimethylamino)propyl)thio)-7-(2,4-difluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 3 mL of dichloromethane cooled down to −78° C. The reaction wasstirred at that temperature for one hour and quenched with an aqueoussaturated solution of NaHCO3, followed by extraction with ethyl acetatethree times. The organic layers were combined, dried with sodium sulfateand the volatiles removed under reduced pressure to afford a residuethat was purified by silica gel chromatography (0-15% MeOH indichloromethane). The title compound was isolated in 12% yield ascolorless oil. m/z (ESI, +ve)=476.1 [M+H]⁺

Step 6:(3R)-11-(2,4-difluorophenyl)-3-(dimethylamino)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(3R)-11-(2,4-difluorophenyl)-3-(dimethylamino)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.The title compound was isolated in 86% yield as a white solid. m/z (ESI,+ve)=458.1 [M+H]⁺

Step 7: tert-butyl(2S,6R)-4-((3R)-11-(2,4-difluorophenyl)-3-(dimethylamino)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where7-(2,4-difluorophenyl)-8-(((R)-2-(dimethylamino)-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 21% yield as a yellow oil. m/z (ESI, +ve)=654.2 [M+H]⁺

Step 8:(3R)-11-(2,4-difluorophenyl)-3-(dimethylamino)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2S,6R)-4-((3R)-11-(2,4-difluorophenyl)-3-(dimethylamino)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.m/z (ESI, +ve)=554.2 [M+H]⁺

Example 1002:(R)-8-(4-acryloylpiperazin-1-yl)-11-(4-fluorophenyl)-3-hydroxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

A 1M solution of Boron tribromide in dichloromethane (0.06 mL) was addedover a solution of(R)-8-(4-acryloylpiperazin-1-yl)-3-(benzyloxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(10 mg) in 1 mL of dichloromethane cooled down to −78° C. The reactionwas stirred at that temperature for one hour and quenched with anaqueous saturated solution of NaHCO3, followed by extraction with ethylacetate three times. The organic layers were combined, dried with sodiumsulfate and the volatiles removed under reduced pressure to afford thetitle compound in 23% yield as white solid. m/z (ESI, +ve)=535.2 [M+H]⁺

Step 1: (R)-2-(benzyloxy)-3-mercaptopropan-1-ol

The title compound was synthesized analogously to example 431, steps1-4, where (2S)-3-chloropropane-1,2-diol was substituted in place of(2R)-3-chloropropane-1,2-diol

Step 2:(R)-3-(benzyloxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (R)-2-(benzyloxy)-3-mercaptopropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 58% yieldas a white solid. m/z (ESI, +ve)=503.1 [M+H]⁺

Step 3: tert-butyl(R)-4-(3-(benzyloxy)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(R)-3-(benzyloxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 95% yield as a yellow solid. m/z (ESI, +ve)=671.2 [M+H]⁺

Step 4:(R)-3-(benzyloxy)-11-(4-fluorophenyl)-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(R)-4-(3-(benzyloxy)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.m/z (ESI, +ve)=571.2 [M+H]⁺

Step 5:(R)-8-(4-acryloylpiperazin-1-yl)-3-(benzyloxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(R)-3-(benzyloxy)-11-(4-fluorophenyl)-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 29% yield as a white solid.

m/z (ESI, +ve)=625.2 [M+H]⁺

Example 1003:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-hydroxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 2, where(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(benzyloxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of(R)-8-(4-acryloylpiperazin-1-yl)-3-(benzyloxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one.The title compound was isolated in 22% yield as a yellow solid. m/z(ESI, +ve)=563.2 [M+H]⁺

1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.33-7.29 (m, 4H), 6.82 (dd,J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 5.41 (s, 1H), 4.61-4.41 (m, 3H), 4.19-4.03 (m, 3H),3.33-3.18 (m, 4H), 2.86-2.82 (m, 1H), 1.44-1.23 (m, 6H).

Step 1:(S)-8-((2-(benzyloxy)-3-hydroxypropyl)thio)-7-(4-fluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 527, step 9where (S)-2-(benzyloxy)-3-mercaptopropan-1-ol was substituted in placeof 2-mercaptoethan-1-ol. The title compound was isolated in 86% yield asa yellow solid. m/z (ESI, +ve)=521.1 [M+H]⁺

Step 2:(S)-3-(benzyloxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was synthesized analogously to example 527, step 10where((S)-8-((2-(benzyloxy)-3-hydroxypropyl)thio)-7-(4-fluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of(R)-7-(4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.The title compound was isolated in 65% yield as a yellow solid. m/z(ESI, +ve)=503.0 [M+H]⁺

Step 3:(S)-3-(benzyloxy)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(S)-3-(benzyloxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 95% yield as a yellow solid. m/z (ESI, +ve)=599.2 [M+H]⁺

Step 4:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(benzyloxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-3-(benzyloxy)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 35% yield as a yellow solid. m/z(ESI, +ve)=653.2 [M+H]⁺

Example 1004:(S)-8-(4-acryloylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(S)-7-(4-fluorophenyl)-8-((3-hydroxy-2-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 1-(piperazin-1-yl)prop-2-en-1-one were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 48% yield as a pale yellow solid. m/z (ESI, +ve)=579.2[M+H]⁺

1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.402-7.38 (m, 4H), 6.88 (dd,J=16.0, 8.0 Hz, 1H), 6.23 (dd, J=16.0, 4.0 Hz, 1H), 5.80 (dd, J=16.0,4.0 Hz, 1H), 4.82-4.72 (m, 2H), 4.64-4.59 (m, 1H), 4.2.4-418 (m, 1H),3.93-3.68 (m, 8H), 3.34 (s, 3H), 3.16-3.12 (m, 1H).

Step 1: (S)-1-((tert-butyldimethylsilyl)oxy)-3-(tritylthio)propan-2-ol

To a mixture oftert-butyl[(2S)-2-hydroxy-3-[(triphenylmethyl)sulfanyl]propoxy]dimethylsilane(25 g, 0.054 mol) and N, N-Diisopropylethylamine (20.9 g, 0.16 mol) inTHF (250 mL) was slowly added bromo(methoxy)methane (13.4 g, 0.11 mol)at 0 C under N2. The mixture was stirred at 0° C. for 0.5 hours. Themixture was stirred at 50° C. for 6 hours, filtered off and theresulting filter cake was washed with ethyl acetate. The resultingorganic solution was concentrated under reduced pressure to afford aresidue that was purified by column chromatography on silica gel (0 to70% ethyl acetate in hexanes) to afford the title compound in 70% yieldas a yellow oil. m/z (ESI, +ve)=531.2 [M+Na]

Step 2: (S)-3-mercapto-2-(methoxymethoxy)propan-1-ol

To a mixture of(5S)-8,8,9,9-tetramethyl-5-{[(triphenylmethyl)sulfanyl]methyl}-2,4,7-trioxa-8-siladecane(10 g, 0.020 mol) and triethylsilane (7.08 g, 0.061 mol) indichloromethane (150 mL) was slowly added trifluoroacetic acid at 0° C.for an hour until the starting material was completely consumed. Thereaction mixture was diluted with water and extracted withdichloromethane twice. The combined organic layers were washed withbrine, dried over sodium sulfate and filtered. After evaporation ofvolatiles under reduced pressure, the crude product was purified bycolumn chromatography on silica gel (0 to 15% methanol indichloromethane) to afford the title compound in 58% yield as acolorless liquid.

¹H NMR (400 MHz, DMSO) δ=5.33 (s, 1H), 4.66-4.62 (m, 2H), 3.56-3.51 (m,1H), 3.50-3.45 (m, 2H), 3.31-3.27 (m, 3H), 2.71-2.67 (m, 1H), 2.59-2.55(m, 1H), 2.24-2.20 (m, 1H).

Step 3:(S)-7-(4-fluorophenyl)-8-((3-hydroxy-2-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-3-mercapto-2-(methoxymethoxy)propan-1-ol were substituted inplace of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 67% yieldas a yellow solid. m/z (ESI, +ve)=497.0 [M+Na]

Step 4:(S)-11-(4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(S)-7-(4-fluorophenyl)-8-((3-hydroxy-2-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 80-% yield as a yellow solid. m/z (ESI, +ve)=557.2 [M+H]⁺

Example 1005:(R)-8-(4-acryloylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(R)-7-(4-fluorophenyl)-8-((3-hydroxy-2-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 1-(piperazin-1-yl)prop-2-en-1-one were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 3% yield as a pale yellow solid. m/z (ESI, +ve)=579.2 [M+H]⁺

1H NMR (400 MHz, DMSO) δ 7.87 (s, 1H), 7.36-7.32 (m, 4H), 6.82 (dd,J=16.0, 8.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, 16.0, 4.0Hz, 1H), 4.74-4.63 (m, 2H), 4.61-4.51 (m, 1H), 4.15-4.12 (m, 1H),3.88-3.65 (m, 7H), 3.48-3.36 (m, 1H), 3.32 (s, 3H), 3.32-3.28 (m, 3H),3.10-3.06 (m, 1H).

Step 1:(R)-11-(4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was synthesized analogously to example 4, steps 1-4wheretert-butyl[(2R)-2-hydroxy-3-[(triphenylmethyl)sulfanyl]propoxy]dimethylsilanein step 1 was substituted in place oftert-butyl[(2S)-2-hydroxy-3-[(triphenylmethyl)sulfanyl]propoxy]dimethylsilane.m/z (ESI, +ve)=557.2 [M+H]⁺

Example 1006:(R)-8-(4-acryloylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(R)-11-(3-chloro-4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand 1-(piperazin-1-yl)prop-2-en-1-one were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 30% yield as a pale yellow solid. m/z (ESI, +ve)=613.2[M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (s, 1H), 7.66-7.56 (m, 2H), 7.39-7.31(m, 1H), 6.83 (dd, J=16.0, 8.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H),5.74 (dd, J=16.0, 4.0 Hz, 1H), 4.69-4.65 (m, 2H), 4.51-4.54 (m, 1H),4.18-4.14 (m, 1H), 3.80-3.37 (m, 10H), 3.28-3.23 (m, 3H), 3.15-3.08 (m,1H).

Step 1: Methyl 3-amino-3′-chloro-4′-fluoro-[1,1′-biphenyl]-4-carboxylate

The title compound was synthesized analogously to example 100, step 1where (3-chloro-4-fluorophenyl)boronic acid was substituted in place of(2,4-difluorophenyl)boronic acid. The title compound was isolated in 92%yield as a brown solid. m/z (ESI, +ve)=280.1 [M+H]⁺

Step 2: Methyl5-amino-3′-chloro-4′-fluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate

The title compound was synthesized analogously to example 100, step 2where Methyl 3-amino-3′-chloro-4′-fluoro-[1,1′-biphenyl]-4-carboxylatewas substituted in place of methyl3-amino-2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylate. The title compoundwas isolated in 91% yield as a brown solid. m/z (ESI, +ve)=406.0 [M+H]⁺

Step 3: Methyl5-acetamido-3′-chloro-4′-fluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate

The title compound was synthesized analogously to example 100, step 3where methyl5-amino-3′-chloro-4′-fluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate wassubstituted in place of 2-amino-4-(2,4-difluorophenyl)-5-iodobenzoate.The title compound was isolated in 98% yield as a brown solid. m/z (ESI,+ve)=414.0 [M+H]⁺

Step 4: Methyl5-acetamido-3′-chloro-4′-fluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate

The title compound was synthesized analogously to example 100, step 4where methyl5-acetamido-3′-chloro-4′-fluoro-2-iodo-[1,1′-biphenyl]-4-carboxylate wassubstituted in place of methyl4-(2,4-difluorophenyl)-2-acetamido-5-iodobenzoate. The title compoundwas isolated in 41% yield as a yellow solid. m/z (ESI, +ve)=390.0 [M+H]⁺

Step 5: methyl5-amino-3′-chloro-4′-fluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate

The title compound was synthesized analogously to example 100, step 5where Methyl5-acetamido-3′-chloro-4′-fluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylatewas substituted in place of methyl5-acetamido-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate.The title compound was isolated in 97% yield as a white solid. m/z (ESI,+ve)=348.0 [M+H]⁺

Step 6: methyl3-amino-3′-chloro-4′-fluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate

The title compound was synthesized analogously to example 100, step 6where methyl5-amino-3′-chloro-4′-fluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylatewas substituted in place of methyl5-amino-2′,4′-difluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate.The title compound was isolated in 75% yield as a white solid. m/z (ESI,+ve)=473.9 [M+H]⁺

Step 7:3-amino-3′-chloro-4′-fluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylicacid

The title compound was synthesized analogously to example 100, step 7where methyl3-amino-3′-chloro-4′-fluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylatewas substituted in place of methyl3-amino-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate.The title compound was isolated in 95% yield as a brown solid. m/z (ESI,+ve)=459.9 [M+H]⁺

Step 8:7-(3-chloro-4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 8where3-amino-3′-chloro-4′-fluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylicacid was substituted in place of3-amino-2′,4′-difluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylicacid. The title compound was isolated in 45% yield as a pale brownsolid. m/z (ESI, +ve)=484.7 [M+H]⁺

Step 9:(R)-7-(3-chloro-4-fluorophenyl)-8-((3-hydroxy-2-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(3-chloro-4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (R)-3-mercapto-2-(methoxymethoxy)propan-1-ol was substituted inplace of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 85% yieldas a white solid. m/z (ESI, +ve)=509.0 [M+H]⁺

Step 10:(R)-11-(3-chloro-4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(R)-7-(3-chloro-4-fluorophenyl)-8-((3-hydroxy-2-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 50% yield as a yellow solid. m/z (ESI, +ve)=491.0 [M+H]⁺

Example 1007:(S)-8-(4-acryloylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(S)-11-(3-chloro-4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand 1-(piperazin-1-yl)prop-2-en-1-one were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 40% yield as a pale yellow solid. m/z (ESI, +ve)=613.2[M+H]⁺

1H NMR (400 MHz, DMSO) δ 7.88 (s, 1H), 7.72-7.51 (m, 2H), 7.38-7.32 (m,1H), 6.82 (dd, J=16.0, 8.0 Hz, 1H), 6.17 (d, J=16.0, 4.0 Hz, 1H), 5.74(dd, J=16.0, 4.0 Hz, 1H), 4.77-4.63 (m, 2H), 4.58-4.54 (m, 1H),4.18-4.14 (m, 1H), 3.87-3.68 (m, 7H), 3.53-3.54 (m, 1H), 3.35-3.18 (m,5H), 3.17-3.04 (m, 1H).

Step 1:(S)-7-(3-chloro-4-fluorophenyl)-8-((3-hydroxy-2-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(3-chloro-4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-3-mercapto-2-(methoxymethoxy)propan-1-ol was substituted inplace of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 85% yieldas a white solid. m/z (ESI, +ve)=509.0 [M+H]⁺

Step 2:(S)-11-(3-chloro-4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(S)-7-(3-chloro-4-fluorophenyl)-8-((3-hydroxy-2-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 80% yield as a yellow solid. m/z (ESI, +ve)=491.0 [M+H]⁺

Example 1008:(3R)-8-(4-acryloylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3R)-11-(5-chloro-2,4-difluorophenyl)-3-(methoxymethoxy)-8-methylene-10-(trifluoromethyl)-3,4,7,8-tetrahydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-oneand 1-(piperazin-1-yl)prop-2-en-1-one were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 13% yield as a pale yellow solid. m/z (ESI, +ve)=631.1[M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 7.91 (s, 1H), 7.81-7.75 (m, 2H), 6.82 (dd,J=16.0, 8.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.74-4.66 (m, 2H), 4.55-4.52 (m, 1H), 4.20-4.16 (m, 1H),3.92-3.66 (m, 8H), 3.31-3.27 (m, 4H), 3.20-3.13 (m, 1H).

Step 1:7-(5-chloro-2,4-difluorophenyl)-8-(((R)-3-hydroxy-2-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(5-chloro-2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(R)-3-mercapto-2-(methoxymethoxy)propan-1-ol were substituted in placeof7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 80% yieldas a white solid. m/z (ESI, +ve)=527.0 [M+H]⁺

Step 2:(3R)-11-(5-chloro-2,4-difluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(5-chloro-2,4-difluorophenyl)-8-(((R)-3-hydroxy-2-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 71% yield as a yellow solid. m/z (ESI, +ve)=509.1 [M+H]⁺

Example 1009:(R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(R)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 82% yield as a yellow solid. m/z(ESI, +ve)=553.2 [M+H]⁺

Step 1:(R)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where7-(4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 82% yield as a yellow solid. m/z (ESI, +ve)=553.2 [M+H]⁺

Example 1010:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(R)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 82% yield as a yellow solid. m/z(ESI, +ve)=607.0 [M+H]⁺

1H NMR (400 MHz, DMSO) δ 8.02 (s, 1H), 7.51-7.16 (m, 4H), 6.81 (dd,J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.69-4.65 (m, 2H), 4.65-4.49 (m, 3H), 4.19-4.15 (m, 1H),4.09-4.05 (m, 2H), 3.37-3.32 (m, 3H), 3.29-3.26 (m, 3H), 3.26-3.21 (m,1H), 3.10-3.05 (m, 1H), 1.40 (s, 6H).

Step 1:(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(S)-11-(4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 70% yield as a yellow solid. m/z (ESI, +ve)=553.1 [M+H]⁺

Example 1011:(3R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(2,4-difluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3R)-11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 10% yield as a white solid. m/z (ESI,+ve)=625.2 [M+H]⁺

1H NMR (400 MHz, DMSO) δ 8.05 (s, 1H), 7.51-7.33 (m, 2H), 7.29-7.25 (m,1H), 6.81 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74(dd, J=16.0, 4.0 Hz, 1H), 4.60-4.55 (m, 5H), 4.21-4.17 (m, 1H),4.09-4.05 (m, 2H), 3.36-3.32 (m, 3H), 3.30-3.26 (m, 3H), 3.26-3.22 (m,1H), 3.15-3.11 (m, 1H), 1.43-1.37 (m, 6H).

Step 1:7-(2,4-difluorophenyl)-8-(((R)-3-hydroxy-2-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 where7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (R)-3-mercapto-2-(methoxymethoxy)propan-1-ol were substituted inplace of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 75% yieldas a yellow solid. m/z (ESI, +ve)=493.1 [M+H]⁺

Step 2:(3R)-11-(2,4-difluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(2,4-difluorophenyl)-8-(((R)-3-hydroxy-2-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 87% yield as a yellow solid. m/z (ESI, +ve)=475.0 [M+H]⁺

Step 3:(3R)-11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3R)-11-(2,4-difluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 45% yield as a yellow solid. m/z (ESI, +ve)=571.2 [M+H]⁺

Example 1012:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(2,4-difluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(2,4-difluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dionewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 31% yield as a white solid. m/z (ESI,+ve)=625.1 [M+H]⁺

1H NMR (400 MHz, DMSO) δ 8.05 (s, 1H), 7.53-7.35 (m, 2H), 7.29-7.25 (m,1H), 6.81 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74(dd, J=16.0, 4.0 Hz, 1H), 4.60-4.55 (m, 6H), 4.19 (s, 1H), 4.10-4.05 (m,2H), 3.61-3.57 (m, 1H), 3.30-3.26 (m, 5H), 3.15-3.11 (m, 1H), 1.40 (d,J=12.0 Hz, 6H).

Step 1:7-(2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 where7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-3-mercapto-2-(methoxymethoxy)propan-1-ol were substituted inplace of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 68% yieldas a yellow solid. m/z (ESI, +ve)=493.1 [M+H]⁺

Step 2:(3S)-11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 10where7-(2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 69% yield as a yellow solid. m/z (ESI, +ve)=475.1 [M+H]⁺

Step 3:(3S)-11-(2,4-difluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 62% yield as a yellow solid. m/z (ESI, +ve)=571.1 [M+H]⁺

Example 1013:(R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(R)-11-(3-chloro-4-fluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 27% yield as a pale yellow solid. m/z(ESI, +ve)=641.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (s, 1H), 7.65-7.56 (m, 2H), 7.39-7.31(m, 1H), 6.82 (dd, J=16.0, 8.0 Hz, 1H), 6.20 (dd, J=16.0, 4.0 Hz, 1H),5.75 (dd, J=16.0, 4.0 Hz, 1H), 4.68-4.52 (m, 6H), 4.21-4.17 (m, 1H),4.09-4.05 (m, 2H), 3.28-3.26 (m, 6H), 3.15-3.07 (m, 1H), 1.40 (s, 6H).

Step 1:(R)-11-(3-chloro-4-fluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(R)-11-(3-chloro-4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 82% yield as a pale yellow solid. m/z (ESI, +ve)=587.1[M+H]⁺

Example 1014:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 55% yield as a yellow solid. m/z(ESI, +ve)=641.2 [M+H]⁺

1H NMR (400 MHz, DMSO) δ=8.02 (s, 1H), 7.70-7.49 (m, 2H), 7.38-7.33 (m,1H), 6.82 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74(dd, J=16.0, 4.0 Hz, 1H), 4.69-4.65 (m, 2H), 4.58-4.54 (m, 3H),4.20-4.16 (m, 1H), 4.10-4.05 (m, 2H), 3.32-3.32 (m, 3H), 3.29-3.27 (m,3H), 3.27-3.23 (m, 1H), 3.12-3.08 (m, 1H), 1.40 (s, 6H).

Step 1:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(S)-11-(3-chloro-4-fluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 55% yield as a pale yellow solid. m/z (ESI, +ve)=587.1[M+H]⁺

Example 1015:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-11-(3-chloro-4-fluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 53% yield as a yellow solid. m/z(ESI, +ve)=659.1 [M+H]⁺

1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.83-7.60 (m, 2H), 6.81 (dd,J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.70-4.52 (m, 6H), 4.21 (s, 1H), 4.07 (d, J=12.0 Hz, 2H),3.62-3.46 (m, 1H), 3.30-3.10 (m, 6H), 1.53-1.30 (m, 6H).

Step 1:7-(5-chloro-2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(5-chloro-2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-3-mercapto-2-(methoxymethoxy)propan-1-ol were substituted inplace of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 71% yieldas a pale yellow solid. m/z (ESI, +ve)=527.1 [M+H]⁺

Step 2:(3S)-11-(5-chloro-2,4-difluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 107-(5-chloro-2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 80% yield as a yellow solid. m/z (ESI, +ve)=509.0 [M+H]⁺

Step 3:(S)-11-(3-chloro-4-fluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-(methoxymethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 82% yield as a yellow solid. m/z (ESI, +ve)=605.1 [M+H]⁺

Example 1016:(R)-8-(4-acryloylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(R)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dionewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 26% yield as a yellow solid. m/z(ESI, +ve)=593.2 [M+H]⁺

1H NMR (400 MHz, DMSO) δ 7.86 (s, 1H), 7.36-7.34 (m, 4H), 6.83 (dd,J=16.0, 8.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.51-4.48 (m, 1H), 3.94-3.51 (m, 12H), 3.48-3.39 (m, 2H),3.29-3.08 (m, 5H).

Step 1:(R)-9,9,10,10-tetramethyl-6-((tritylthio)methyl)-2,5,8-trioxa-9-silaundecane

To a suspension of NaH (0.17 mol) in THF (60 mL) at 0° C. was added asolution of(R)-1-((tert-butyldimethylsilyl)oxy)-3-(tritylthio)propan-2-ol (0.13mol) in THF (60 mL). The mixture was stirred at 0° C. for 30 minutes.DMF (120 mL) was added followed by 1-bromo-2-methoxyethane (0.32 mol).The mixture was stirred at room temperature for 5 hours, quenched withwater and extracted with ethyl acetate twice. The combined organiclayers were washed with brine, dried over sodium sulfate andconcentrated to afford a residue that was purified with silica gelchromatography (0-15% ethyl acetate in hexanes). The title compound wasisolated in 83% yield as yellow oil. m/z (ESI, +ve)=545.3 [M+Na]⁺

Step 2: (R)-3-mercapto-2-(2-methoxyethoxy)propan-1-ol

To 0° C. mixture of(R)-9,9,10,10-tetramethyl-6-((tritylthio)methyl)-2,5,8-trioxa-9-silaundecane(0.11 mol) in dichloromethane/TFA (60/20 mL) was added triethyl silane(0.34 mol). The mixture was stirred at room temperature for 30 m mutes,diluted with water and extracted with dichloromethane five times. Thecombined organic layers were concentrated to afford a residue that waspurified by silica gel column chromatography (0-7% methanol indichloromethane) to afford the title compound in 75% yield as yellow oil

Step 3:(R)-7-(4-fluorophenyl)-8-((3-hydroxy-2-(2-methoxyethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (R)-3-mercapto-2-(2-methoxyethoxy)propan-1-ol were substituted inplace of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 92% yieldas a yellow solid. m/z (ESI, +ve)=489.1 [M+H]⁺

Step 4:(R)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(R)-7-(4-fluorophenyl)-8-((3-hydroxy-2-(2-methoxyethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 83% yield as a yellow solid. m/z (ESI, +ve)=471.1 [M+H]⁺

Step 5:(R)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(R)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand piperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 82% yield as a pale yellow solid. m/z (ESI, +ve)=639.2[M+H]⁺

Example 1017:(S)-8-(4-acryloylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 21% yield as a yellow solid. m/z(ESI, +ve)=593.2 [M+H]⁺

1H NMR (400 MHz, DMSO) δ 7.86 (s, 1H), 7.36-7.34 (m, 4H), 6.82 (dd,J=16.0, 8.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.51-4.48 (m, 1H), 3.94-3.61 (m, 11H), 3.44-3.37 (m, 4H),3.28-3.23 (m, 3H), 3.11-3.08 (m, 1H).

Step 1:(S)-7-(4-fluorophenyl)-8-((3-hydroxy-2-(2-methoxyethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 527, step 9where (S)-3-mercapto-2-(2-methoxyethoxy)propan-1-ol was substituted inplace of 2-mercaptoethan-1-ol. The title compound was isolated in 82%yield as a pale yellow solid. m/z (ESI, +ve)=489.1 [M+H]⁺

Step 2:(S)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was synthesized analogously to example 527, step 10where(S)-7-(4-fluorophenyl)-8-((3-hydroxy-2-(2-methoxyethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of(R)-7-(4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.The title compound was isolated in 63% yield as a yellow solid. m/z(ESI, +ve)=471.1 [M+H]⁺

Step 3: tert-butyl(S)-4-(11-(4-fluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(S)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 71% yield as a yellow solid. m/z (ESI, +ve)=639.2 [M+H]⁺

Step 4:(S)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(S)-4-(11-(4-fluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 91% yield as a yellow solid. m/z(ESI, +ve)=539.2 [M+H]⁺

Example 1018:(3R)-8-(4-acryloylpiperazin-1-yl)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3R)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 34% yield as a yellow solid. m/z(ESI, +ve)=611.0 [M+H]⁺

1H NMR (400 MHz, DMSO) δ 7.89 (s, 1H), 7.46-7.42 (m, 2H), 7.28-7.24 (m,1H), 6.82 (dd, J=16.0, 8.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H), 5.74(dd, J=16.0, 4.0 Hz, 1H), 4.49-4.45 (m, 1H), 3.80-3.76 (m, 11H),3.45-3.41 (m, 2H), 3.35-3.31 (m, 2H), 3.25-3.21 (m, 3H), 3.19-3.10 (m,1H).

Step 1:7-(2,4-difluorophenyl)-8-(((R)-3-hydroxy-2-(2-methoxyethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 where7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (R)-3-mercapto-2-(2-methoxyethoxy)propan-1-ol were substituted inplace of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 66% yieldas a white solid. m/z (ESI, +ve)=507.1 [M+H]⁺

Step 2:(3R)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was synthesized analogously to example 527, step 10where7-(2,4-difluorophenyl)-8-(((R)-3-hydroxy-2-(2-methoxyethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of(R)-7-(4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.The title compound was isolated in 65% yield as a yellow solid. m/z(ESI, +ve)=489.1 [M+H]⁺

Step 3: tert-butyl4-((3R)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3R)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 52% yield as a yellow solid. m/z (ESI, +ve)=489.1 [M+H]⁺

Step 4:(3R)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(S)-4-(11-(4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 94% yield as a yellow solid. m/z(ESI, +ve)=557.2 [M+H]⁺

Example 1019:(3S)-8-(4-acryloylpiperazin-1-yl)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 19% yield as a yellow solid. m/z(ESI, +ve)=611.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.47-7.37 (m, 2H), 7.28-7.26(m, 1H), 6.82 (dd, J=16.0, 8.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H),5.74 (d, J=16.0, 4.0 Hz, 1H), 4.48-4.44 (m, 1H), 3.97-3.62 (m, 11H),3.44-3.43 (m, 2H), 3.38-3.33 (m, 2H), 3.23 (s, 2H), 3.18-3.15 (m, 2H).

Step 1:7-(2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-(2-methoxyethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-3-mercapto-2-(2-methoxyethoxy)propan-1-ol were substituted inplace of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 56% yieldas a yellow solid. m/z (ESI, +ve)=507.1 [M+H]⁺

Step 2:(3S)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-(2-methoxyethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 86% yield as a yellow solid. m/z (ESI, +ve)=489.1 [M+H]⁺

Step 3: tert-butyl4-((3S)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 83% yield as a yellow solid. m/z (ESI, +ve)=657.2 [M+H]⁺

Step 4:(3S)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl4-((3S)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 92% yield as a yellow oil. m/z (ESI,+ve)=557.2 [M+H]⁺

Example 1020:(R)-8-(4-acryloylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

Step 1:(R)-7-(3-chloro-4-fluorophenyl)-8-((3-hydroxy-2-(2-methoxyethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(3-chloro-4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (R)-3-mercapto-2-(2-methoxyethoxy)propan-1-ol were substituted inplace of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 76% yieldas a white solid. m/z (ESI, +ve)=523 [M+H]⁺

Step 2:(R)-11-(3-chloro-4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(R)-7-(3-chloro-4-fluorophenyl)-8-((3-hydroxy-2-(2-methoxyethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 52% yield as a yellow solid. m/z (ESI, +ve)=506.0 [M+H]⁺

Step 3: tert-butyl(R)-4-(11-(3-chloro-4-fluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(R)-11-(3-chloro-4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 74% yield as a yellow solid. m/z (ESI, +ve)=673.2 [M+H]⁺

Step 4:(R)-11-(3-chloro-4-fluorophenyl)-3-(2-methoxyethoxy)-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(R)-4-(11-(3-chloro-4-fluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 98% yield as a yellow solid. m/z(ESI, +ve)=539.2 [M+H]⁺

Example 1021:(S)-8-(4-acryloylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-11-(3-chloro-4-fluorophenyl)-3-(2-methoxyethoxy)-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 51% yield as a yellow solid. m/z(ESI, +ve)=627.2 [M+H]⁺

1H NMR (400 MHz, DMSO-d₆) δ 7.87 (s, 1H), 7.61-7.57 (m, 2H), 7.36 (s,1H), 6.83 (dd, J=16.0, 8.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H), 5.74(dd, J=16.0, 4.0 Hz, 1H), 4.53-4.49 (m, 1H), 3.98-3.60 (m, 11H),3.46-3.42 (m, 2H), 3.38-3.34 (m, 3H), 3.26-3.22 (m, 3H), 3.14-3.10 (m,1H).

Step 1:(S)-7-(3-chloro-4-fluorophenyl)-8-((3-hydroxy-2-(2-methoxyethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(3-chloro-4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-3-mercapto-2-(2-methoxyethoxy)propan-1-ol were substituted inplace of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 78% yieldas a white solid. m/z (ESI, +ve)=523.0 [M+H]⁺

Step 2:(S)-11-(3-chloro-4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(S)-7-(3-chloro-4-fluorophenyl)-8-((3-hydroxy-2-(2-methoxyethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 76% yield as a yellow solid. m/z (ESI, +ve)=527.0 [M+H]⁺

Step 3: tert-butyl(S)-4-(11-(3-chloro-4-fluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(S)-11-(3-chloro-4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 49% yield as a yellow solid. m/z (ESI, +ve)=673.2 [M+H]⁺

Step 4:(S)-11-(3-chloro-4-fluorophenyl)-3-(2-methoxyethoxy)-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(S)-4-(11-(3-chloro-4-fluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 94% yield as a yellow solid. m/z(ESI, +ve)=573.1 [M+H]⁺

Example 1022:(3R)-8-(4-acryloylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3R)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in XX % yield as a yellow solid. m/z(ESI, +ve)=645.1 [M+H]⁺

1H NMR (400 MHz, DMSO) δ 7.90 (s, 1H), 7.81-7.75 (m, 2H), 6.82 (dd,J=16.0, 8.0 Hz, 1H), 6.17 (d, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0, 4.0Hz, 1H), 4.54-4.42 (m, 1H), 3.98 (s, 1H), 3.91-3.54 (m, 10H), 3.43-3.41(m, 2H), 3.37-3.33 (m, 2H), 3.24 (s, 3H), 3.22-3.14 (m, 1H).

Step 1:7-(5-chloro-2,4-difluorophenyl)-8-(((R)-3-hydroxy-2-(2-methoxyethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(5-chloro-2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (R)-3-mercapto-2-(2-methoxyethoxy)propan-1-ol were substituted inplace of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 63% yieldas a white solid. m/z (ESI, +ve)=541.0 [M+H]⁺

Step 2:(3R)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(5-chloro-2,4-difluorophenyl)-8-(((R)-3-hydroxy-2-(2-methoxyethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 75% yield as a yellow solid. m/z (ESI, +ve)=523.0 [M+H]⁺

Step 3: tert-butyl4-((3R)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3R)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 90% yield as a yellow solid. m/z (ESI, +ve)=691.2 [M+H]⁺

Step 4:(3R)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl4-((3R)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 88% yield as a yellow solid. m/z(ESI, +ve)=591.1 [M+H]⁺

Example 1023:(3S)-8-(4-acryloylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 36% yield as a yellow solid. m/z(ESI, +ve)=645.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.80-7.75 (m, 2H), 6.82 (dd,J=16.0, 8.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.49-4.46 (m, 1H), 4.03-3.94 (m, 1H), 3.92-3.56 (m, 10H),3.46-3.42 (m, 2H), 3.40-3.35 (m, 1H), 3.33-3.30 (m, 1H), 3.24 (s, 3H),3.21-3.16 (m, 1H)

Step 1:7-(5-chloro-2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-(2-methoxyethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(5-chloro-2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-3-mercapto-2-(2-methoxyethoxy)propan-1-ol were substituted inplace of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 86% yieldas a white solid. m/z (ESI, +ve)=541.1 [M+H]⁺⁻

Step 2:(3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(5-chloro-2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-(2-methoxyethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 70% yield as a yellow solid. m/z (ESI, +ve)=523.1 [M+H]⁺

Step 3: tert-butyl4-((3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 84% yield as a yellow solid. m/z (ESI, +ve)=691.2 [M+H]⁺

Step 4:(3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl4-((3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 92% yield as a yellow solid. m/z(ESI, +ve)=591.1 [M+H]⁺

Example 1024:(R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(R)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 31% yield as a yellow solid. m/z(ESI, +ve)=621.2 [M+H]⁺

1H NMR (400 MHz, DMSO) δ 8.02 (s, 1H), 7.35-7.32 (m, 4H), 6.82 (dd,J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.61-4.57 (m, 2H), 4.49-4.46 (m, 1H), 4.09-4.04 (m, 2H),3.96-3.94 (m, 1H), 3.61 (s, 1H), 3.43-3.41 (m, 2H), 3.32-3.25 (m, 5H),3.25-3.21 (m, 3H), 3.11-3.05 (m, 1H), 1.40 (s, 6H).

Step 1: tert-butyl(2S,6R)-4-((R)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(R)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate weresubstituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 73% yield as a yellow solid. m/z (ESI, +ve)=667.2 [M+H]⁺

Step 2:(R)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2S,6R)-4-((R)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 95% yield as a yellow solid. m/z(ESI, +ve)=567.0 [M+H]⁺

Example 1025:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 69% yield as a yellow solid. m/z(ESI, +ve)=667.2 [M+H]⁺

Step 1: tert-butyl(2S,6R)-4-((S)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(S)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 69% yield as a yellow solid. m/z (ESI, +ve)=667.2 [M+H]⁺

Step 2:(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2S,6R)-4-((S)-11-(4-fluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 92% yield as a yellow solid. m/z(ESI, +ve)=567.2 [M+H]⁺

Example 1026:(3R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3R)-11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 26% yield as a yellow solid. m/z(ESI, +ve)=639.2 [M+H]⁺

1H NMR (400 MHz, DMSO) δ 8.04 (s, 1H), 7.46-7.42 (m, 2H), 7.29-7.25 (m,1H), 6.81 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74(dd, J=16.0, 4.0 Hz, 1H), 4.66-4.38 (m, 3H), 4.15-3.93 (m, 3H),3.64-3.60 (m, 2H), 3.45-3.40 (m, 2H), 3.35-3.31 (m, 3H), 3.25-3.21 (m,4H), 3.17-3.13 (m, 1H), 1.42-1.38 (m, 6H).

Step 1: tert-butyl(2S,6R)-4-((3R)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3R)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (2R,6S)-2,6-dimethylpiperazine-1-carboxylate weresubstituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 79% yield as a yellow solid. m/z (ESI, +ve)=685.2 [M+H]⁺

Step 2:(3R)-11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2S,6R)-4-((3R)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 94% yield as a yellow solid. m/z(ESI, +ve)=585.2 [M+H]⁺

Example 1027:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to example 84 where(3S)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated as yellow solid in 18% yield. m/z (ESI,+ve)=639.2 [M+H]⁺

1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.52-7.33 (m, 2H), 7.29-7.22(m, 1H), 6.81 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H),5.74 (dd, J=16.0, 4.0 Hz, 1H), 4.77-4.23 (m, 4H), 4.18-3.90 (m, 3H),3.79-3.55 (m, 2H), 3.50-3.36 (m, 3H), 3.34-3.30 (m, 1H), 3.28-3.25 (m,1H), 3.24-3.19 (m, 3H), 3.18-3.09 (m, 1H), 1.60-1.13 (m, 6H).

Step 1: tert-butyl4-((3S)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 75% yield as a yellow solid. m/z (ESI, +ve)=685.2 [M+H]⁺

Step 2:(3S)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl4-((3S)-11-(2,4-difluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 97% yield as a yellow solid. m/z(ESI, +ve)=585.1 [M+H]⁺

Example 1028:(R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(R)-11-(3-chloro-4-fluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 88% yield as a yellow solid. m/z(ESI, +ve)=655.2 [M+H]⁺

1H NMR (400 MHz, DMSO) δ 8.02 (s, 1H), 7.61-7.56 (m, 2H), 7.37-7.32 (m,1H), 6.82 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74(dd, J=16.0, 4.0 Hz, 1H), 4.61-4.57 (m, 2H), 4.51-4.47 (m, 1H),4.09-4.04 (m, 2H), 4.02-3.97 (m, 1H), 3.64-3.60 (m, 2H), 3.43-3.39 (m,3H), 3.27-3.24 (m, 5H), 3.12-3.09 (m, 2H), 1.40 (s, 6H).

Step 1:(R)-11-(3-chloro-4-fluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(R)-11-(3-chloro-4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 88% yield as a yellow solid. m/z (ESI, +ve)=601.2 [M+H]⁺

Example 1029:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-11-(3-chloro-4-fluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 88% yield as a yellow solid. m/z(ESI, +ve)=655.2 [M+H]⁺

1H NMR (400 MHz, DMSO) δ 8.02 (s, 1H), 7.60-7.56 (m, 2H), 7.37 (s, 1H),6.82 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd,J=16.0, 4.0 Hz, 1H), 4.65-4.44 (m, 3H), 4.07-4.01 (m, 3H), 3.64-3.60 (m,2H), 3.45-3.41 (m, 2H), 3.37-3.32 (m, 3H), 3.31-3.27 (m, 1H), 3.25-3.21(m, 3H), 3.17-3.05 (m, 1H), 1.39 (s, 6H).

Step 1:(S)-11-(3-chloro-4-fluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(S)-11-(3-chloro-4-fluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 65% yield as a yellow solid. m/z (ESI, +ve)=601.2 [M+H]⁺

Example 1030:(3R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3R)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 28% yield as a yellow solid. m/z(ESI, +ve)=673.2 [M+H]⁺

1H NMR (400 MHz, DMSO-d₆) δ 8.04 (s, 1H), 7.80-7.76 (m, 2H), 6.81 (dd,J=16.0, 8.0 Hz, 1H), 6.19 (d, J=16.0, 4.0 Hz, 1H), 5.74 (d, J=16.0, 4.0Hz, 1H), 4.65-4.54 (m, 2H), 4.51-4.43 (m, 1H), 4.13-3.95 (m, 3H),3.69-3.54 (m, 2H), 3.44-3.42 (m, 2H), 3.35-3.32 (m, 2H), 3.31-3.13 (m,6H), 1.52-1.28 (m, 6H).

Step 1: tert-butyl(2S,6R)-4-((3R)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where3R)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate weresubstituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 93% yield as a yellow solid. m/z (ESI, +ve)=719.2 [M+H]⁺

Step 2:(3R)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2S,6R)-4-((3R)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 90% yield as a yellow solid. m/z(ESI, +ve)=619.1 [M+H]⁺

Example 1031:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to example 84 where(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated as a pale yellow solid in 21% yield. m/z(ESI, +ve)=673.0 [M+H]⁺

1H NMR (400 MHz, DMSO-d₆) δ 8.04 (s, 1H), 7.80-7.76 (m, 2H), 6.81 (dd,J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.68-4.42 (m, 3H), 4.13-3.98 (m, 3H), 3.65-3.61 (m, 2H),3.45-3.41 (m, 2H), 3.36-3.30 (m, 4H), 3.25-3.22 (m, 3H), 3.19-3.15 (m,1H), 1.43-1.37 (m, 6H).

Step 1: tert-butyl(2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate weresubstituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 60% yield as a yellow solid. m/z (ESI, +ve)=719.3 [M+H]⁺

Step 2:(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(2-methoxyethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-methoxyethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 95% yield as a yellow solid. m/z(ESI, +ve)=619.1 [M+H]⁺

Example 1032:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-amino-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

Over a solution of tert-butyl((S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)carbamate(0.03 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid(0.3 mL) and the resulting mixture stirred at room temperature for onehour. The reaction was quenched with water and extracted withdichloromethane three times. The organic layers were combined, washedwith brine and dried over sodium sulfate. The volatiles were removedunder reduced pressure to afford a residue that was purified bypreparative HPLC to afford the title compound as a yellow solid. m/z(ESI, +ve)=562.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (s, 1H), 7.43-7.25 (m, 4H), 6.82 (dd,J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=8.0, 4.0Hz, 1H), 4.61-4.57 (m, 2H), 4.42-4.38 (m, 1H), 4.05 (d, J=12.0 Hz, 2H),3.27-3.17 (m, 5H), 2.79 (s, 1H), 1.44-1.37 (m, 6H).

Step 1: (R)-1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-ol

TBDPSCl (56.7 mmol) was added over a 0° C. solution of(2R)-3-[(triphenylmethyl)sulfanyl]propane-1,2-diol (57.1 mmol) andimidazole (141.2 mmol) in DMF (100 mL). The mixture was stirred at roomtemperature for 16 hours and diluted with water. The reaction mixturewas extracted with ethyl acetate three times and the combined organiclayers dried over sodium sulfate to afford a residue that was purifiedby silica gel chromatography (0-15% ethyl acetate in hexanes). The titlecompound was isolated as a colorless oil in 98% yield. m/z (ESI,+ve)=611.2 [M+H]⁺

Step 2: (S)-(2-azido-3-(tritylthio)propoxy)(tert-butyl)diphenylsilane

Over a 0° C. solution of(R)-1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-ol (52.6mmol) and triphenyl phosphine (105 mmol) in THF (300 mL) was added DEAD(105.2 mmol). After 20 minutes, diphenylphosphoryl azide (69.1 mmol) wasslowly added and the mixture stirred at room temperature for 16 hours.The reaction was quenched by the addition of water and the resultingmixture was extracted with ethyl acetate three times. The combinedorganic layers were dried over sodium sulfate to afford a residue thatwas purified by silica gel chromatography (0-10% ethyl acetate inhexanes). The title compound was isolated as a colorless oil in 90%yield as a colorless oil.

Step 3: (S)-2-azido-3-((tert-butyldiphenylsilyl)oxy)propane-1-thiol

Triethylsilane (0.15 mmol) was added over a solution of(S)-(2-azido-3-(tritylthio)propoxy)(tert-butyl)diphenylsilane (53.8mmol) in dichloromethane (150 mL) and trifluoroacetic acid (35 mL) atroom temperature. After 20 minutes, the reaction was quenched with waterand extracted with dichloromethane three times. The combined organiclayers were washed with brine and dried over sodium sulfate to afford aresidue that was purified by silica gel chromatography (0-8% methanol indichloromethane). The title compound was isolated as a colorless oil in50% yield as a yellow oil.

Step 4:(S)-8-((2-amino-3-((tert-butyldiphenylsilyl)oxy)propyl)thio)-7-(4-fluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where(S)-8-((2-amino-3-((tert-butyldiphenylsilyl)oxy)propyl)thio)-7-(4-fluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-2-azido-3-((tert-butyldiphenylsilyl)oxy)propane-1-thiol weresubstituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 37% yieldas a green solid. m/z (ESI, +ve)=668.0 [M+H]⁺

Step 5: tert-butyl(S)-(1-((tert-butyldiphenylsilyl)oxy)-3-((7-(4-fluorophenyl)-2,4-dioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-8-yl)thio)propan-2-yl)carbamate

Boc anhydride (1.66 mmol) and triethylamine (3.27 mmol) were added overa solution of(S)-8-((2-amino-3-((tert-butyldiphenylsilyl)oxy)propyl)thio)-7-(4-fluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(1.11 mmol) in THF (15 mL). The mixture was stirred at room temperaturefor 16 hours and the volatiles were removed under reduced pressure. Theresulting residue was purified by reverse phase chromatography (70-98%acetonitrile in water with 0.1% TFA) to afford the title compounds as acolorless oil in 52% yield. m/z (ESI, +ve)=789.9 [M+H]⁺

Step 6: tert-butyl(S)-(1-((7-(4-fluorophenyl)-2,4-dioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-8-yl)thio)-3-hydroxypropan-2-yl)carbamate

A 1M THF solution of tetrabutylammonium fluoride (0.85 mmol) was addedwas added over a solution of tert-butyl(S)-(1-((tert-butyldiphenylsilyl)oxy)-3-((7-(4-fluorophenyl)-2,4-dioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-8-yl)thio)propan-2-yl)carbamate(0.57 mmol) in THF (8 mL) at room temperature. After 30 minutes themixture was concentrated under reduced pressure and the resultingresidue was purified by reverse phase chromatography (40-70%acetonitrile in water with 0.1% TFA) to afford the title compounds as awhite solid in 99% yield. m/z (ESI, +ve)=552.0 [M+H]⁺

Step 7: tert-butyl(S)-(11-(4-fluorophenyl)-6,8-dioxo-10-(trifluoromethyl)-3,4,7,8-tetrahydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)carbamate

The title compound was prepared analogously to Example 100, step 10where tert-butyl(S)-(1-((7-(4-fluorophenyl)-2,4-dioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-8-yl)thio)-3-hydroxypropan-2-yl)carbamatewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 85% yield as a white solid after purification by reverse phasechromatography (30-60% acetonitrile in water with 0.1% TFA). m/z (ESI,+ve)=534.0 [M+H]⁺

Step 8: tert-butyl((S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)carbamate

The title compound was prepared analogously to Example 100, step 21where tert-butyl(S)-(11-(4-fluorophenyl)-6,8-dioxo-10-(trifluoromethyl)-3,4,7,8-tetrahydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)carbamateand 1-((2S,6R)-2,6-dimethylpiperazin-1-yl)prop-2-en-1-one weresubstituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated a yellow oil. m/z (ESI, +ve)=291.1 [M+H]⁺

Example 1033:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(2-(dimethylamino)ethoxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-3-(2-(dimethylamino)ethoxy)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 7% yield as a white solid. m/z (ESI,+ve)=634.3 [M+H]⁺

1H NMR (400 MHz, DMSO) δ 8.02 (s, 1H), 7.35 (d, J=8.0 Hz, 4H), 6.82 (dd,J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.64-4.44 (m, 3H), 4.09-4.05 (m, 2H), 3.97-3.93 (m, 1H),3.55-3.51 (m, 2H), 3.35-3.31 (m, 4H), 3.12-3.08 (m, 1H), 2.43-2.40 (m,2H), 2.16 (s, 6H), 1.40 (s, 3H), 1.27-1.16 (m, 3H).

Step 1:(S)-2-((1-((tert-butyldimethylsilyl)oxy)-3-(tritylthio)propan-2-yl)oxy)-N,N-dimethylethan-1-amine

Sodium hydride (0.11 mmol) was added over a solution oftert-butyl[(2S)-2-hydroxy-3-[(triphenylmethyl)sulfanyl]propoxy]dimethylsilane(0.011 mmol) in dioxane (50 mL) at room temperature. After 30 minutes(2-bromoethyl)dimethylamine hydrobromide (0.04 mmol) was added and themixture was stirred at 95° C. for two additional hours. The reaction wasstopped by the addition of water and extracted with dichloromethanethree times. The organic layers were combined, washed with brine anddried over sodium sulfate. Evaporation of volatiles under reducedpressure afforded a residue that was purified by silica gelchromatography to afford the title compound as a yellow oil in 65%yield.

Step 2: (S)-2-(2-(dimethylamino)ethoxy)-3-mercaptopropan-1-ol

Triethylsilane (0.022 mmol) was added over a solution of(S)-2-((1-((tert-butyldimethylsilyl)oxy)-3-(tritylthio)propan-2-yl)oxy)-N,N-dimethylethan-1-amine(0.008 mmol) in dichloromethane (30 mL) and trifluoroacetic acid (10 mL)at room temperature. After 30 minutes, water was added and the mixtureextracted with dichloromethane three times. The organic layers werecombined, washed with brine and dried over sodium sulfate. Evaporationof volatiles under reduced pressure afforded the title compound as acolorless oil in 98% yield.

Step 3:(S)-8-((2-(2-(dimethylamino)ethoxy)-3-hydroxypropyl)thio)-7-(4-fluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-2-(2-(dimethylamino)ethoxy)-3-mercaptopropan-1-ol weresubstituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 67% yieldas a yellow solid. m/z (ESI, +ve)=502.1 [M+H]⁺

Step 4:(S)-3-(2-(dimethylamino)ethoxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(S)-8-((2-(2-(dimethylamino)ethoxy)-3-hydroxypropyl)thio)-7-(4-fluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 71% yield as a yellow solid. m/z (ESI, +ve)=484.1 [M+H]⁺

Step 5:(S)-3-(2-(dimethylamino)ethoxy)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(S)-3-(2-(dimethylamino)ethoxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2S,6R)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 4% yield as a yellow solid. m/z (ESI, +ve)=580.3 [M+H]⁺

Example 1034:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(2,4-difluorophenyl)-3-(2-(dimethylamino)ethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(2,4-difluorophenyl)-3-(2-(dimethylamino)ethoxy)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 4% yield as a yellow solid. m/z (ESI,+ve)=652.2 [M+H]⁺

1H NMR (400 MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.52-7.33 (m, 2H), 7.32-7.22(m, 1H), 6.81 (dd, J=16.0, 8.0 Hz, 1H), 6.20 (dd, J=16.0, 4.0 Hz, 1H),5.75 (dd, J=16.0, 4.0 Hz, 1H), 4.72-4.36 (m, 3H), 4.17-3.83 (m, 3H),3.62-3.43 (m, 3H), 3.28-3.05 (m, 4H), 2.43-2.35 (m, 2H), 2.18-2.10 (m,6H), 1.51-1.29 (m, 6H).

Step 1:7-(2,4-difluorophenyl)-8-(((S)-2-(2-(dimethylamino)ethoxy)-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-2-(2-(dimethylamino)ethoxy)-3-mercaptopropan-1-ol weresubstituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 90% yieldas a yellow solid after purification by reverse phase silica gelchromatography (36% acetonitrile in water with 0.1% TFA). m/z (ESI,+ve)=520.1 [M+H]⁺

Step 2:(3S)-11-(2,4-difluorophenyl)-3-(2-(dimethylamino)ethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(2,4-difluorophenyl)-8-(((S)-2-(2-(dimethylamino)ethoxy)-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 20% yield as a yellow solid after purification by reverse phasesilica gel chromatography (29% acetonitrile in water with 0.1% TFA). m/z(ESI, +ve)=502.1 [M+H]⁺

Step 3:(3S)-11-(2,4-difluorophenyl)-3-(2-(dimethylamino)ethoxy)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(2,4-difluorophenyl)-3-(2-(dimethylamino)ethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2S,6R)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 53% yield as a yellow solid after purification by reversephase silica gel chromatography (27% acetonitrile in water with 0.1%TFA). m/z (ESI, +ve)=598.2 [M+H]⁺

Example 1035:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-(2-(dimethylamino)ethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-11-(3-chloro-4-fluorophenyl)-3-(2-(dimethylamino)ethoxy)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 16% yield as a yellow solid. m/z(ESI, +ve)=668.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 8.01 (s, 1H), 7.58-7.56 (m, 2H), 7.34-7.30(m, 1H), 6.82 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H),5.74 (dd, J=16.0, 4.0 Hz, 1H), 4.63-4.55 (m, 2H), 4.50-4.46 (m, 1H),4.10-4.02 (m, 2H), 3.96-3.94 (m, 1H), 3.54-3.51 (m, 1H), 3.30-3.24 (m,2H), 3.17-3.08 (m, 2H), 2.57-2.53 (m, 1H), 2.46-2.43 (m, 1H), 2.39-2.36(m, 2H), 2.13 (s, 6H), 1.40 (s, 6H).

Step 1:(S)-7-(3-chloro-4-fluorophenyl)-8-((2-(2-(dimethylamino)ethoxy)-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(3-chloro-4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-2-(2-(dimethylamino)ethoxy)-3-mercaptopropan-1-ol weresubstituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 71% yieldas a white solid. m/z (ESI, +ve)=536.1 [M+H]⁺

Step 2:(S)-11-(3-chloro-4-fluorophenyl)-3-(2-(dimethylamino)ethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(S)-7-(3-chloro-4-fluorophenyl)-8-((2-(2-(dimethylamino)ethoxy)-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 87% yield as a yellow solid. m/z (ESI, +ve)=518.1 [M+H]⁺

Step 3:(S)-11-(3-chloro-4-fluorophenyl)-3-(2-(dimethylamino)ethoxy)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(S)-11-(3-chloro-4-fluorophenyl)-3-(2-(dimethylamino)ethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2S,6R)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 23% yield as a yellow solid. m/z (ESI, +ve)=614.2 [M+H]⁺

Example 1036:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(2-(dimethylamino)ethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-(dimethylamino)ethoxy)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 8% yield as a yellow solid. m/z (ESI,+ve)=686.2 [M+H]⁺

1H NMR (400 MHz, dmso) δ=8.04 (s, 1H), 7.81-7.75 (m, 2H), 6.81 (dd,J=16.6, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.59 (m, 2H), 4.49-4.46 (m, 1H), 4.13-3.92 (m, 4H), 3.59(m, 2H), 3.28-3.12 (m, 3H), 2.52-2.51 (m, 1H), 2.40-2.36 (m, 2H), 2.14(s, 6H), 1.43-1.39 (m, 6H).

Step 1:7-(5-chloro-2,4-difluorophenyl)-8-(((S)-2-(2-(dimethylamino)ethoxy)-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(5-chloro-2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-2-(2-(dimethylamino)ethoxy)-3-mercaptopropan-1-ol weresubstituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 91% yieldas a white solid. m/z (ESI, +ve)=554.1 [M+H]⁺

Step 2:(3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-(dimethylamino)ethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(5-chloro-2,4-difluorophenyl)-8-(((S)-2-(2-(dimethylamino)ethoxy)-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 47% yield as a yellow solid. m/z (ESI, +ve)=536.0 [M+H]⁺

Step 3:(3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-(dimethylamino)ethoxy)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-(dimethylamino)ethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2S,6R)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 47% yield as a yellow solid. m/z (ESI, +ve)=536.0 [M+H]⁺

Example 1037:(R)-8-(4-acryloylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(R)-10-chloro-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 25% yield as a yellow solid. MassSpectrum (ESI) m/z=549.1 [M+H]⁺

Step 1: tert-butyl(R)-4-(11-(4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(R)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 60% yield as a yellow solid. m/z (ESI, +ve)=595.2 [M+H]⁺

Step 2:(R)-11-(4-fluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(R)-4-(11-(4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 95% yield as a yellow solid. m/z(ESI, +ve)=494.9 [M+H]⁺

Example 1038:(S)-8-(4-acryloylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-10-chloro-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 28% yield as a yellow solid. MassSpectrum (ESI) m/z=549.1 [M+H]⁺

1H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.36-7.32 (m, 4H), 6.83 (dd,J=16.0, 8.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.57-4.45 (m, 1H), 3.99-3.61 (m, 9H), 3.39-3.33 (m, 5H),3.16-3.03 (m, 1H).

Step 1: tert-butyl(S)-4-(11-(4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(S)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 56% yield as a yellow solid. m/z (ESI, +ve)=595.2 [M+H]⁺

1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.46-7.32 (m, 4H), 4.54-4.45(m, 1H), 3.83-3.72 (m, 6H), 3.55-3.45 (m, 4H), 3.29-3.24 (m, 3H),3.12-3.04 (m, 1H), 3.03-2.96 (m, 1H), 1.43 (s, 9H).

Step 2:(S)-11-(4-fluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(S)-4-(11-(4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 97% yield as a yellow solid. m/z(ESI, +ve)=494.9 [M+H]⁺

Example 1039:(R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-chloro-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(R)-10-chloro-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 35% yield as a yellow solid. MassSpectrum (ESI) m/z=543.2 [M+H]⁺

1H NMR (400 MHz, DMSO) δ7.79 (s, 1H), 7.37-7.34 (m, 4H), 6.81 (dd,J=16.0 Hz, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.62-4.41 (m, 3H), 4.07-4.02 (m, 2H), 3.88-3.80 (m, 1H),3.33-3.28 (m, 7H), 3.10-3.06 (m, 1H), 1.41-1.36 (m, 6H).

Step 1:(R)-10-chloro-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(R)-10-chloro-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 90% yield as a yellow solid. Mass Spectrum (ESI) m/z=489.2[M+H]⁺

Example 1040:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-chloro-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-10-chloro-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 28% yield as a yellow solid. m/z(ESI, +ve)=543.2 [M+H]⁺

1H NMR (400 MHz, DMSO) δ 7.79 (s, 1H), 7.37-7.35 (m, 3H), 6.81 (dd,J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.58-4.54 (m, 2H), 4.47-4.44 (m, 1H), 4.04-4.02 (m, 2H),3.86-3.83 (m, 1H), 3.30-3.28 (m, 3H), 3.09-3.05 (m, 1H), 2.49-2.36 (m,4H), 1.41-1.36 (m, 6H).

Step 1:(S)-10-chloro-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(S)-10-chloro-11-(4-fluorophenyl)-3-methoxy-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2S,6R)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 82% yield as a yellow solid. m/z (ESI, +ve)=489.2 [M+H]⁺

Example 1041:(R)-8-(4-acryloylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(R)-11-(3-chloro-4-fluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 48% yield as a yellow solid. m/z(ESI, +ve)=583.1 [M+H]⁺

1H NMR (400 MHz, DMSO) δ=7.87 (s, 1H), 7.71-7.48 (m, 2H), 7.42-7.27 (m,1H), 6.83 (dd, J=16.0, 8.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H), 5.74(dd, J=16.0, 4.0 Hz, 1H), 4.62-4.46 (m, 1H), 4.12-3.50 (m, 9H),3.48-3.30 (m, 5H), 3.21-3.04 (m, 1H).

Step 1:(R)-7-(3-chloro-4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(3-chloro-4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (R)-3-mercapto-2-methoxypropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 74% yieldas a white solid. m/z (ESI, +ve)=479.0 [M+H]⁺

Step 2:(R)-11-(3-chloro-4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(R)-7-(3-chloro-4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 74% yield as a yellow solid. m/z (ESI, +ve)=461.1 [M+H]⁺

Step 3: tert-butyl(R)-4-(11-(3-chloro-4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(R)-11-(3-chloro-4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 87% yield as a yellow solid. m/z (ESI, +ve)=629.2 [M+H]⁺

Step 4:(R)-11-(3-chloro-4-fluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(R)-4-(11-(3-chloro-4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated as a yellow solid and used in the nextstep without further purification. m/z (ESI, +ve)=529.2 [M+H]⁺

Example 1042:(S)-8-(4-acryloylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-11-(3-chloro-4-fluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 39% yield as a yellow solid. m/z(ESI, +ve)=583.1 [M+H]⁺

1H NMR (400 MHz, DMSO-d₆) δ 7.87 (s, 1H), 7.67-7.51 (m, 2H), 7.46-7.35(m, 1H), 6.83 (dd, J=16.0, 8.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H),5.74 (dd, J=16.0, 4.0 Hz, 1H), 4.53-4.49 (m, 1H), 3.92-3.53 (m, 9H),3.49-3.34 (m, 5H), 3.16-3.01 (m, 1H).

Step 1:(S)-7-(3-chloro-4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(3-chloro-4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-3-mercapto-2-methoxypropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 74% yieldas a white solid. m/z (ESI, +ve)=479.1 [M+H]⁺

Step 2:(S)-11-(3-chloro-4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(S)-7-(3-chloro-4-fluorophenyl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 83% yield as a yellow solid. m/z (ESI, +ve)=461.1 [M+H]⁺

Step 3: tert-butyl(S)-4-(11-(3-chloro-4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(S)-11-(3-chloro-4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 87% yield as a yellow solid. m/z (ESI, +ve)=629.2 [M+H]⁺

Step 4:(S)-11-(3-chloro-4-fluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(S)-4-(11-(3-chloro-4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated as a yellow solid and used in the nextstep without further purification. m/z (ESI, +ve)=529.1 [M+H]⁺

Example 1043:(R)-8-(4-acryloylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(R)-11-(3-chloro-4-fluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 48% yield as a yellow solid. m/z(ESI, +ve)=583.1 [M+H]⁺

1H NMR (400 MHz, DMSO) δ=7.87 (s, 1H), 7.71-7.48 (m, 2H), 7.42-7.27 (m,1H), 6.83 (dd, J=16.0, 8.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H), 5.74(dd, J=16.0, 4.0 Hz, 1H), 4.62-4.46 (m, 1H), 4.12-3.50 (m, 9H),3.48-3.30 (m, 5H), 3.21-3.04 (m, 1H).

Step 1: tert-butyl(R)-4-(11-(3-chloro-4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(R)-11-(3-chloro-4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 87% yield as a yellow solid. m/z (ESI, +ve)=629.2 [M+H]⁺

Step 2:(R)-11-(3-chloro-4-fluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(R)-4-(11-(3-chloro-4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated as a yellow solid. m/z (ESI, +ve)=529.2[M+H]⁺

Example 1044:(S)-8-(4-acryloylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-11-(3-chloro-4-fluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 39% yield as a yellow solid. m/z(ESI, +ve)=583.1 [M+H]⁺

1H NMR (400 MHz, DMSO-d₆) δ 7.87 (s, 1H), 7.67-7.51 (m, 2H), 7.46-7.35(m, 1H), 6.83 (dd, J=16.0, 8.0 Hz, 1H), 6.17 (dd, J=16.0, 4.0 Hz, 1H),5.74 (dd, J=16.0, 4.0 Hz, 1H), 4.53-4.49 (m, 1H), 3.92-3.53 (m, 9H),3.49-3.34 (m, 5H), 3.16-3.01 (m, 1H).

Step 1: tert-butyl(S)-4-(11-(3-chloro-4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(S)-11-(3-chloro-4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl piperazine-1-carboxylate were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in XX % yield as a yellow solid. m/z (ESI, +ve)=629.1 [M+H]⁺

Step 2:(S)-11-(3-chloro-4-fluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(S)-4-(11-(3-chloro-4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)piperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 99% yield as a yellow solid. m/z(ESI, +ve)=529.1 [M+H]⁺

Example 1045:(R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(R)-11-(3-chloro-4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dionewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 39% yield as a yellow solid. m/z(ESI, +ve)=611.2 [M+H]⁺

1H NMR (400 MHz, DMSO) δ=8.02 (s, 1H), 7.74-7.48 (m, 2H), 7.43-7.25 (m,1H), 6.81 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74(dd, J=16.0, 4.0 Hz, 1H), 4.73-4.39 (m, 3H), 4.21-4.00 (m, 2H),3.93-3.76 (m, 1H), 3.55-3.31 (m, 5H), 3.30-3.19 (m, 2H), 3.18-3.05 (m,1H), 1.71-1.10 (m, 6H).

Step 1:(R)-11-(3-chloro-4-fluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(R)-11-(3-chloro-4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 25% yield as a yellow solid. m/z (ESI, +ve)=557.1 [M+H]⁺

Example 1046:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-11-(3-chloro-4-fluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 26% yield as a yellow solid. m/z(ESI, +ve)=611.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (s, 1H), 7.60-7.56 (m, 2H), 7.37-7.33(m, 1H), 6.82 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H),5.74 (dd, J=16.0, 4.0 Hz, 1H), 4.66-4.47 (m, 3H), 4.09-4.05 (m, 2H),3.86-3.82 (m, 1H), 3.35-3.31 (m, 7H), 3.15-3.11 (m, 1H), 1.40 (s, 6H).

Step 1:(S)-11-(3-chloro-4-fluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(S)-11-(3-chloro-4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 82% yield as a yellow solid; m/z (ESI, +ve)=557.1 [M+H]⁺.

TABLE 9 Example Number CAF (% binding after 60 min) 1001 84 1002 97 100395 1004 97 1005 97 1006 90 1007 97 1008 92 1009 96 1010 96 1011 97 101295 1013 95 1014 96 1015 84 1016 98 1017 98 1018 96 1019 97 1020 97 102197 1022 85 1023 97 1024 97 1025 96 1026 95 1027 96 1028 96 1029 96 103096 1031 95 1032 92 1033 96 1034 97 1035 97 1036 97 1037 96 1038 97 103996 1040 96 1041 97 1042 97 1043 97 1044 97 1045 96 1046 96

Example 1200:(E)-11-(2,4-difluorophenyl)-8-(9-(4-fluorobut-2-enoyl)-7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where11-(2,4-difluorophenyl)-8-(7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-oneand (E)-4-fluorobut-2-enoyl chloride were substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-oneand acryloyl chloride. The title compound was isolated in 10% yield as ayellow solid. m/z (ESI, +ve)=623.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO) δ7.85-7.81 (m, 1H), 7.49-7.34 (m, 2H), 7.27 (s, 1H), 6.98-6.56 (m, 2H),5.26-5.08 (m, 2H), 4.76-4.72 (m, 1H), 4.55-4.49 (m, 2H), 4.09-3.85 (m,2H), 3.53-3.40 (m, 2H), 3.23-3.19 (m, 2H), 3.08-2.89 (m, 3H), 2.75-2.68(m, 2H), 2.06-1.97 (m, 2H). ¹H NMR (400 MHz, DMSO) δ 7.85-7.81 (m, 1H),7.49-7.34 (m, 2H), 7.27 (s, 1H), 6.98-6.56 (m, 2H), 5.26-5.08 (m, 2H),4.76-4.72 (m, 1H), 4.55-4.49 (m, 2H), 4.09-3.85 (m, 2H), 3.53-3.40 (m,2H), 3.23-3.19 (m, 2H), 3.08-2.89 (m, 3H), 2.75-2.68 (m, 2H), 2.06-1.97(m, 2H).

Example 1201:(S)-8-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-11-(3-chloro-4-fluorophenyl)-8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 32% yield as a yellow solid. m/z(ESI, +ve)=611.2 [M+H]+. ¹H NMR (400 MHz, DMSO-d₆) δ 7.83 (s, 1H),7.60-7.56 (m, 2H), 7.35 (s, 1H), 6.81 (dd, J=16.0, 8.0 Hz, 1H), 6.18(dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0, 4.0 Hz, 1H), 4.78-4.74 (m,1H), 4.51-4.48 (m, 3H), 4.11-3.72 (m, 5H), 3.28-3.13 (m, 5H), 1.27 (s,6H).

Step 1: tert-butyl(2R,5S)-4-((S)-11-(3-chloro-4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,5-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(S)-11-(3-chloro-4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate weresubstituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 81% yield as a yellow solid. m/z (ESI, +ve)=657.2 [M+H]⁺.

Step 2:(S)-11-(3-chloro-4-fluorophenyl)-8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2R,5S)-4-((S)-11-(3-chloro-4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,5-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 94% yield as a yellow solid. m/z(ESI, +ve)=557.1 [M+H]+.

Example 1202:(S)-8-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 54% yield as a yellow solid. m/z(ESI, +ve)=577.2 [M+H]+. ¹H NMR (400 MHz, DMSO-d₆) δ 7.83 (s, 1H), 7.34(d, J=8.0 Hz, 4H), 6.89-6.72 (m, 1H), 6.18 (dd, J=16.0 Hz, 4.0 Hz, 1H),5.76-5.72 (m, 1H), 4.76 (s, 1H), 4.66-4.39 (m, 3H), 4.14-3.72 (m, 5H),3.42-3.34 (m, 4H), 3.12 (m 1H), 1.26 (s, 6H).

Step 1: tert-butyl(2R,5S)-4-((S)-11-(4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,5-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(S)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate weresubstituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 88% yield as a yellow solid. m/z (ESI, +ve)=623.2 [M+H]+.

Step 2:(S)-8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2R,5S)-4-((S)-11-(4-fluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,5-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 88% yield as a yellow solid. m/z(ESI, +ve)=523.1 [M+H]+.

Example 1203:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-ethoxy-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-ethoxy-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 28% yield as a yellow solid. m/z(ESI, +ve)=591.2 [M+H]+.

¹H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.44-7.24 (m, 4H), 6.82 (dd,J=16.0 Hz, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0,4.0 Hz, 1H), 4.71-4.53 (m, 2H), 4.49-4.43 (m, 1H), 4.15-4.00 (m, 2H),3.93-3.88 (m, 1H), 3.59-3.28 (m, 2H), 3.33-3.17 (m, 4H), 3.09-3.01 (m,1H), 1.52-1.22 (m, 6H), 1.10 (t, J=8.0 Hz, 3H).

Step 1: (S)-3-mercapto-2-methoxypropan-1-ol

The title compound was synthesized analogously to example 464, steps 1to 3, where in step 3 ethyl iodide was used in place of methyl iodide.m/z (ESI, +ve)=137.1 [M+H]+.

Step 2:(S)-8-((2-ethoxy-3-hydroxypropyl)thio)-7-(4-fluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-2-ethoxy-3-mercaptopropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 88% yieldas a white solid. m/z (ESI, +ve)=459.0 [M+H]+

Step 3:(S)-3-ethoxy-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(S)-8-((2-ethoxy-3-hydroxypropyl)thio)-7-(4-fluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 90% yield as a yellow solid. m/z (ESI, +ve)=441.0 [M+H]+.

Step 4:(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-ethoxy-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(S)-3-ethoxy-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 90% yield as a yellow solid. m/z (ESI, +ve)=537.2 [M+H]+.

Example 1204:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-3-ethoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-11-(3-chloro-4-fluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-ethoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 24% yield as a yellow solid. m/z(ESI, +ve)=625.2 [M+H]+. ¹H NMR (400 MHz, DMSO) δ 8.02 (s, 1H),7.60-7.56 (m, 2H), 7.36-7.28 (m, 1H), 6.81 (dd, J=16.0, 8.0 Hz, 1H),6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0, 4.0 Hz, 1H), 4.59 (s,2H), 4.50-4.47 (m, 1H), 4.09-4.03 (m, 2H), 3.96-3.93 (m, 1H), 3.54 (s,1H), 3.36-3.31 (m, 2H), 3.30-3.20 (m, 3H), 3.16-3.14 (m, 1H), 1.40 (s,6H), 1.10 (t, J=8.0 Hz, 3H).

Step 1:(S)-7-(3-chloro-4-fluorophenyl)-8-((2-ethoxy-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(3-chloro-4-fluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-2-ethoxy-3-mercaptopropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 71% yieldas a white solid. m/z (ESI, +ve)=493.0 [M+H]+

Step 2:(S)-11-(3-chloro-4-fluorophenyl)-3-ethoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(S)-7-(3-chloro-4-fluorophenyl)-8-((2-ethoxy-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 67% yield as a yellow solid. m/z (ESI, +ve)=475.0 [M+H]+

Step 3:(S)-11-(3-chloro-4-fluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-ethoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(S)-11-(3-chloro-4-fluorophenyl)-3-ethoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 69% yield as a yellow solid. m/z (ESI, +ve)=571.0 [M+H]+.

Example 1205:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(2,4-difluorophenyl)-3-ethoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-ethoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 47 yield as a yellow solid. m/z (ESI,+ve)=609.2 [M+H]+. ¹H NMR (400 MHz, DMSO) δ=8.04 (s, 1H), 7.45-7.41 (m,2H), 7.26 (t, J=8.0 Hz, 1H), 6.81 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd,J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0, 4.0 Hz, 1H), 4.59 (s, 2H),4.48-4.44 (m, 1H), 4.08-4.04 (m, 2H), 3.97-3.93 (m, 1H), 3.49-3.43 (m,3H), 3.28-3.24 (m, 3H), 3.17-3.06 (m, 1H), 1.53-1.32 (m, 6H), 1.10 (t,J=8.0 Hz, 3H).

Step 1:7-(2,4-difluorophenyl)-8-(((S)-2-ethoxy-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-2-ethoxy-3-mercaptopropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 93% yieldas a white solid. m/z (ESI, +ve)=477.1 [M+H]+.

Step 2:(3S)-11-(2,4-difluorophenyl)-3-ethoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(2,4-difluorophenyl)-8-(((S)-2-ethoxy-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 75% yield as a yellow solid. m/z (ESI, +ve)=459.1 [M+H]+.

Step 3:(3S)-11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-ethoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(2,4-difluorophenyl)-3-ethoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 74% yield as a yellow solid. m/z (ESI, +ve)=555.2 [M+H]+.

Example 1206:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-ethoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-ethoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 34% yield as a yellow solid. m/z(ESI, +ve)=643.2 [M+H]+. ¹H NMR (400 MHz, DMSO) δ 8.05 (s, 1H),7.80-7.76 (m, 2H), 6.81 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0Hz, 1H), 5.75 (dd, J=16.0, 4.0 Hz, 1H), 4.76-4.28 (m, 4H), 4.12-3.90 (m,3H), 3.57-3.53 (m, 3H), 3.31-3.12 (m, 3H), 1.50-1.25 (m, 6H), 1.11 (t,J=8.0 Hz, 3H).

Step 1:7-(5-chloro-2,4-difluorophenyl)-8-(((S)-2-ethoxy-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(5-chloro-2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-2-ethoxy-3-mercaptopropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 82% yieldas a white solid. m/z (ESI, +ve)=511.0 [M+H]+

Step 2:(3S)-11-(5-chloro-2,4-difluorophenyl)-3-ethoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(5-chloro-2,4-difluorophenyl)-8-(((S)-2-ethoxy-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 97% yield as a yellow solid. m/z (ESI, +ve)=493.0 [M+H]+.

Step 3:(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-ethoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-ethoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 77% yield as a yellow solid. m/z (ESI, +ve)=589.2 [M+H]+.

Example 1207:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-fluoropyridin-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(5-fluoropyridin-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 14% yield as a yellow solid. m/z(ESI, +ve)=578.2 [M+H]+. ¹H NMR (400 MHz, DMSO) δ=8.73 (s, 1H), 8.04 (s,1H), 7.92 (t, J=4.0 Hz, 1H), 7.61-7.57 (m, 1H), 6.82 (dd, J=16.0, 8.0Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0, 4.0 Hz, 1H),4.69-4.46 (m, 3H), 4.08-4.04 (m, 2H), 3.88-3.84 (m, 1H), 3.37-3.33 (m,5H), 3.29-3.26 (m, 2H), 3.13-3.09 (m, 1H), 1.40 (m, 6H). Step 1: methyl2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate.

A mixture of methyl 2-amino-4-bromobenzoate (0.17 mol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.26 mol),Pd(dppf)Cl₂ (17.4 mmol) and KOAc (0.52 mol) in 1,4-dioxane (500 mL) wasstirred at 100° C. for 16 hours. The mixture was filtered andconcentrated to afford a residue that was purified by silica gelchromatography (0-10% ethyl acetate in hexanes). The title compound wasisolated in quantitative yield as a yellow solid. m/z (ESI, +ve)=278.2[M+H]+.

Step 2: methyl 2-amino-4-(5-fluoropyridin-2-yl)benzoate

A mixture of methyl2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.14mol), 2-bromo-5-fluoropyridine (0.11 mol), Pd(dppf)Cl₂ (24.5 mmol) andK₃PO₄ (0.37 mol) in 1,4-dioxane:H₂O (300 mL:30 mL) was stirred at 100°C. for 16 hours. The mixture was cooled to room temperature and thesolids filtered. The filtrate was concentrated to afford a residue thatwas purified by silica gel column (0-8% ethyl acetate in hexanes) toafford the title compound in 83% yield as a white solid. m/z (ESI,+ve)=247.1 [M+H]⁺.

Step 3: methyl 2-amino-4-(5-fluoropyridin-2-yl)-5-iodobenzoate

NIS (0.13 mol) was added over a solution of methyl2-amino-4-(5-fluoropyridin-2-yl)benzoate (0.13 mol) in DMF (150 mL) andthe reaction was stirred at room temperature for 16 hours. The reactionwas quenched with water and extracted with ethyl acetate three times.The organic layers were dried over sodium sulfate and concentrated.Purification of the crude material by silica gel chromatography (0-15%ethyl acetate in hexanes) afforded the title compound in 90% yield as ayellow solid. m/z (ESI, +ve)=373.0 [M+H]+.

Step 4: methyl 2-acetamido-4-(5-fluoropyridin-2-yl)-5-iodobenzoate

To a mixture of methyl 2-amino-4-(5-fluoropyridin-2-yl)-5-iodobenzoate(0.055 mol) in AcOH (150 mL) was added acetic anhydride (0.082 mol) andthe reaction was stirred at 100° C. for 2 hours. The mixture was cooledto room temperature, diluted with water and filtered. The filtrate cakewas dried under reduced pressure to afford the title compound in 99%yield as a white solid. m/z (ESI, +ve)=415.0 [M+H]+.

Step 5: methyl2-acetamido-4-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)benzoate

To a mixture of methyl2-acetamido-4-(5-fluoropyridin-2-yl)-5-iodobenzoate (26.5 mmol), CuI(36.8 mmol) and tetrabutylammonium iodide (10.6 mmol) in HMPA (50 mL)was slowly added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (260.4mmol). The mixture was stirred at 90° C. for 1.5 hours and cooled downto room temperature, quenched with water and filtered. The filtrate wasextracted with ethyl acetate three times and the combined organic layerswere washed with water, brine, dried over sodium sulfate andconcentrated to afford a residue that was purified by silica gelchromatography (0-15% ethyl acetate in hexanes) to afford the titlecompound in 53% yield as a yellow solid. m/z (ESI, +ve)=357.1 [M+H]+.

Step 6: methyl2-amino-4-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)benzoate

A mixture of methyl2-acetamido-4-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)benzoate (28.1mmol) in MeOH (50 mL) and concentrated aqueous HCl (50 mL) was stirredat 80° C. for 2 hours. The mixture was cooled down to room temperatureand the pH adjusted to 7 by the addition of sodium carbonate. Themixture was extracted with ethyl acetate three times and the combinedorganic layers were washed with water, brine, dried over sodium sulfateand concentrated to afford the title compound in 97% yield as a yellowoil. m/z (ESI, +ve)=315.0 [M+H]+.

Step 7: methyl2-amino-4-(5-fluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoate

To a mixture of methyl2-amino-4-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)benzoate (27.1 mmol)in AcOH (100 mL) was added N-iodosuccinamide (44.4 mol). The reactionwas stirred at room temperature for 36 hours and the volatiles removedunder reduced pressure. The resulting residue was redissolved in ethylacetate and sequentially washed with saturated aqueous Na₂S₂O₃, waterand brine. The organic layer was dried over sodium sulfate andconcentrated to afford a residue that was purified by silica gelchromatography (0-15% ethyl acetate in hexanes) affording the titlecompound in 88% yield as a yellow solid. m/z (ESI, +ve)=441.0 [M+H]+.

Step 8:2-amino-4-(5-fluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoic acid

To a mixture of methyl2-amino-4-(5-fluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoate(23.8 mmol) in MeOH:THF (30 mL:30 mL) was added aqueous 0.01M NaOH(0.238 mol) and the reaction was stirred at room temperature for 30minutes. The pH of the mixture was adjusted to 5 by the addition of 6MHCl and the solution was extracted with ethyl acetate three times. Thecombined organic layers were washed with water, brine, dried over sodiumsulfate and concentrated to afford the title compound in 99% yield as ayellow oil. m/z (ESI, +ve)=427.0 [M+H]+.

Step 9:7-(5-fluoropyridin-2-yl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

A mixture of2-amino-4-(5-fluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoic acid(20.4 mmol) and urea (1.67 mol) was heated at 200° C. for 2 hours. Thereaction was cooled down to 90° C. and diluted with 600 mL ofmethanol:ethyl acetate (1:1). The mixture was allowed to cool down toroom temperature slowly and stirred for another 3 hours. Afterfiltration, the volatiles were removed under reduced pressure and thecrude material purified by reverse phase silica gel chromatography toafford the title compound as a white solid in 20% yield. m/z (ESI,+ve)=452.0 [M+H]+.

Step 10:(S)-7-(5-fluoropyridin-2-yl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(5-fluoropyridin-2-yl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-3-mercapto-2-methoxypropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 94% yieldas a yellow solid. m/z (ESI, +ve)=446.0 [M+H]+.

Step 11:(S)-11-(5-fluoropyridin-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(S)-7-(5-fluoropyridin-2-yl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 14% yield as a yellow solid. m/z (ESI, +ve)=428.0 [M+H]+.

Step 12:(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(5-fluoropyridin-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(S)-11-(5-fluoropyridin-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 85% yield as a yellow solid. m/z (ESI, +ve)=524.1 [M+H]⁺.

Example 1208:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-11-(4-(trifluoromethyl)thiazol-2-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-11-(4-(trifluoromethyl)thiazol-2-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 50% yield as a yellow solid. m/z(ESI, +ve)=634.0 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.05(s, 1H), 6.81 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H),5.74 (d, J=16.0, 4.0 Hz, 1H), 4.58-4.51 (m, 3H), 4.08-4.04 (m, 2H),3.91-3.83 (m, 1H), 3.55-3.43 (m, 1H), 3.33-3.28 (m, 6H), 3.23-3.19 (m,1H), 1.40 (s, 6H).

Step 1: 2-bromo-4-(trifluoromethyl)thiazole

To a 0° C. mixture of 4-(trifluoromethyl)thiazol-2-amine (0.089 mol) andCuBr₂ (0.18 mol) in acetonitrile (150 mL) was slowly added tert-butylnitrite (0.18 mol). After 30 minutes at 0° C., the reaction was stirredat room temperature for 2.5 hours. The mixture was quenched with waterextracted with dichloromethane three times and the combined organiclayers were washed with brine, dried over sodium sulfate andconcentrated under reduced pressure to afford the title compound as ayellow oil that was used in the next step without further purification.

Step 2: methyl 2-amino-4-(4-(trifluoromethyl)thiazol-2-yl)benzoate

The title compound was prepared analogously to Example 1207, step 2,where 2-bromo-4-(trifluoromethyl)thiazole was substituted in place of2-bromo-5-fluoropyridine. The title compound was isolated in 22% yield(last two steps) as a yellow solid. m/z (ESI, +ve)=303.0 [M+H]+.

Step 3: methyl2-amino-5-iodo-4-(4-(trifluoromethyl)thiazol-2-yl)benzoate

The title compound was prepared analogously to Example 207, step 3,where methyl 2-amino-4-(4-(trifluoromethyl)thiazol-2-yl)benzoate wassubstituted in place of methyl 2-amino-4-(5-fluoropyridin-2-yl)benzoate.The title compound was isolated in 90% yield as a yellow solid. m/z(ESI, +ve)=428.9 [M+H]⁺.

Step 4: methyl2-acetamido-5-iodo-4-(4-(trifluoromethyl)thiazol-2-yl)benzoate

The title compound was prepared analogously to Example 207, step 4,where methyl 2-amino-5-iodo-4-(4-(trifluoromethyl)thiazol-2-yl)benzoatewas substituted in place of methyl2-amino-4-(5-fluoropyridin-2-yl)-5-iodobenzoate. The title compound wasisolated in 97% yield as a yellow solid. m/z (ESI, +ve)=470.9 [M+H]⁺.

Step 5: methyl2-acetamido-5-(trifluoromethyl)-4-(4-(trifluoromethyl)thiazol-2-yl)benzoate

The title compound was prepared analogously to Example 207, step 5,where methyl2-acetamido-5-iodo-4-(4-(trifluoromethyl)thiazol-2-yl)benzoate wassubstituted in place of methyl2-acetamido-4-(5-fluoropyridin-2-yl)-5-iodobenzoate. The title compoundwas isolated in 79% yield as a yellow solid. m/z (ESI, +ve)=413.0[M+H]+.

Step 6: methyl2-amino-5-(trifluoromethyl)-4-(4-(trifluoromethyl)thiazol-2-yl)benzoate

The title compound was prepared analogously to Example 207, step 6,where methyl2-acetamido-5-(trifluoromethyl)-4-(4-(trifluoromethyl)thiazol-2-yl)benzoatewas substituted in place of methyl2-acetamido-4-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)benzoate. Thetitle compound was isolated in 94% yield as a yellow solid. m/z (ESI,+ve)=371.0 [M+H]+.

Step 7: methyl2-amino-3-iodo-5-(trifluoromethyl)-4-(4-(trifluoromethyl)thiazol-2-yl)benzoate

The title compound was prepared analogously to Example 207, step 7,where methyl2-amino-5-(trifluoromethyl)-4-(4-(trifluoromethyl)thiazol-2-yl)benzoatewas substituted in place of methyl2-amino-4-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)benzoate. The titlecompound was isolated in 89% yield as a yellow solid. m/z (ESI,+ve)=496.9 [M+H]+.

Step 8:2-amino-3-iodo-5-(trifluoromethyl)-4-(4-(trifluoromethyl)thiazol-2-yl)benzoicacid

The title compound was prepared analogously to Example 207, step 8,where methyl2-amino-3-iodo-5-(trifluoromethyl)-4-(4-(trifluoromethyl)thiazol-2-yl)benzoatewas substituted in place of methyl2-amino-4-(5-fluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoate. Thetitle compound was isolated in 97% yield as a yellow solid. m/z (ESI,+ve)=482.9 [M+H]+

Step 9:8-iodo-6-(trifluoromethyl)-7-(4-(trifluoromethyl)thiazol-2-yl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 207, step 9,where2-amino-3-iodo-5-(trifluoromethyl)-4-(4-(trifluoromethyl)thiazol-2-yl)benzoicacid was substituted in place of2-amino-4-(5-fluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoic acid.The title compound was isolated in 48% yield as a yellow solid. m/z(ESI, +ve)=507.9 [M+H]+.

Step 10:(S)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)-7-(4-(trifluoromethyl)thiazol-2-yl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where8-iodo-6-(trifluoromethyl)-7-(4-(trifluoromethyl)thiazol-2-yl)quinazoline-2,4(1H,3H)-dioneand (S)-3-mercapto-2-methoxypropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 69% yieldas a yellow solid. m/z (ESI, +ve)=502.1 [M+H]+.

Step 11:(S)-3-methoxy-10-(trifluoromethyl)-11-(4-(trifluoromethyl)thiazol-2-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(S)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)-7-(4-(trifluoromethyl)thiazol-2-yl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 62% yield as a yellow solid. m/z (ESI, +ve)=484.0 [M+H]+.

Step 12:(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-11-(4-(trifluoromethyl)thiazol-2-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(S)-3-methoxy-10-(trifluoromethyl)-11-(4-(trifluoromethyl)thiazol-2-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 79% yield as a yellow solid. m/z (ESI, +ve)=580.1 [M+H]+.

Example 1209:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-fluoro-4-methylpyridin-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(5-fluoro-4-methylpyridin-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 25% yield as a yellow solid. m/z(ESI, +ve)=592.0 [M+H]+. ¹H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.03(s, 1H), 7.52-7.45 (m, 1H), 6.82 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd,J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=16.0, 4.0 Hz, 1H), 4.62-4.47 (m, 4H),4.08-4.02 (m, 2H), 3.85-3.84 (m, 1H), 3.33-3.25 (m, 6H), 3.12-3.09 (m,1H), 2.36 (s, 3H), 1.40 (s, 6H).

Step 1: methyl 2-amino-4-(5-fluoro-4-methylpyridin-2-yl)benzoate

The title compound was prepared analogously to Example 1207, step 2,where 2-bromo-4-(trifluoromethyl)thiazole was substituted in place of2-bromo-5-fluoro-4-methylpyridine. The title compound was isolated in88% yield (last two steps) as a yellow solid. m/z (ESI, +ve)=261.1[M+H]+.

Step 2: methyl 2-amino-4-(5-fluoro-4-methylpyridin-2-yl)-5-iodobenzoate

The title compound was prepared analogously to Example 1207, step 3,where methyl 2-amino-4-(5-fluoro-4-methylpyridin-2-yl)benzoate wassubstituted in place of methyl 2-amino-4-(5-fluoropyridin-2-yl)benzoate.The title compound was isolated in 53% yield as a yellow solid. m/z(ESI, +ve)=387.0 [M+H]+.

Step 3: methyl2-acetamido-4-(5-fluoro-4-methylpyridin-2-yl)-5-iodobenzoate

The title compound was prepared analogously to Example 1207, step 4,where methyl 2-amino-4-(5-fluoro-4-methylpyridin-2-yl)-5-iodobenzoatewas substituted in place of methyl2-amino-4-(5-fluoropyridin-2-yl)-5-iodobenzoate. The title compound wasisolated in 98% yield as a yellow solid. m/z (ESI, +ve)=429.0 [M+H]+.

Step 4: methyl2-acetamido-4-(5-fluoro-4-methylpyridin-2-yl)-5-(trifluoromethyl)benzoate

The title compound was prepared analogously to Example 1207, step 5,where methyl2-acetamido-4-(5-fluoro-4-methylpyridin-2-yl)-5-iodobenzoate wassubstituted in place of methyl2-acetamido-4-(5-fluoropyridin-2-yl)-5-iodobenzoate. The title compoundwas isolated in 56% yield as a yellow solid. m/z (ESI, +ve)=371.1[M+H]+.

Step 5: methyl2-amino-4-(5-fluoro-4-methylpyridin-2-yl)-5-(trifluoromethyl)benzoate

The title compound was prepared analogously to Example 1207, step 6,where methyl2-acetamido-4-(5-fluoro-4-methylpyridin-2-yl)-5-(trifluoromethyl)benzoatewas substituted in place of methyl2-acetamido-4-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)benzoate. Thetitle compound was isolated in 78% yield as a yellow solid. m/z (ESI,+ve)=329.1 [M+H]+.

Step 6: methyl2-amino-4-(5-fluoro-4-methylpyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoate

The title compound was prepared analogously to Example 1207, step 7,where methyl2-amino-4-(5-fluoro-4-methylpyridin-2-yl)-5-(trifluoromethyl)benzoatewas substituted in place of methyl2-amino-4-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)benzoate. The titlecompound was isolated in 75% yield as a yellow solid. m/z (ESI,+ve)=455.0 [M+H]+.

Step 7:2-amino-4-(5-fluoro-4-methylpyridin-2-yl)-3-iodo-5-trifluoromethyl)benzoicacid

The title compound was prepared analogously to Example 1207, step 8,where methyl2-amino-4-(5-fluoro-4-methylpyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoatewas substituted in place of methyl2-amino-4-(5-fluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoate. Thetitle compound was isolated in 97% yield as a yellow solid. m/z (ESI,+ve)=441.0 [M+H]+.

Step 8:7-(5-fluoro-4-methylpyridin-2-yl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 1207, step 9,where2-amino-4-(5-fluoro-4-methylpyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoicacid was substituted in place of2-amino-4-(5-fluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoic acid.The title compound was isolated in 14% yield as a yellow solid. m/z(ESI, +ve)=466.0 [M+H]+.

Step 9:(S)-7-(5-fluoro-4-methylpyridin-2-yl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(5-fluoro-4-methylpyridin-2-yl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-3-mercapto-2-methoxypropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 87% yieldas a yellow solid. m/z (ESI, +ve)=460.0 [M+H]+.

Step 10:(S)-11-(5-fluoro-4-methylpyridin-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(S)-7-(5-fluoro-4-methylpyridin-2-yl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 60% yield as a yellow solid. m/z (ESI, +ve)=442.0 [M+H]+.

Step 11:(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(5-fluoro-4-methylpyridin-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(S)-11-(5-fluoro-4-methylpyridin-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 75% yield as a yellow solid. m/z (ESI, +ve)=538.0 [M+H]+.

Example 1210:(3S)-8-(9-acryloyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-8-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 38% yield as a yellow solid. m/z(ESI, +ve)=624.9 [M+H]+. ¹H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H),7.80-7.73 (m, 2H), 6.90-6.78 (dd, J=16.0, 8.0 Hz, 1H), 6.25 (dd, J=16.0Hz, 4.0 Hz, 1H), 5.80 (dd, J=16.0 Hz, 4.0 Hz, 1H), 4.74-4.23 (m, 6H),4.10-3.92 (m, 2H), 3.88-3.84 (m, 1H), 3.77-3.58 (m, 3H), 3.57-3.35 (m,4H), 3.20-3.16 (m, 2H).

Step 1: tert-butyl7-((3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate weresubstituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 82% yield as a yellow solid. m/z (ESI, +ve)=688.9 [M+H]+.

Step 2:(3S)-8-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl7-((3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 88% yield as a yellow solid. m/z(ESI, +ve)=588.9 [M+H]+.

Example 1211:(3S)-8-((4aR,7aS)-4-acryloyl-6,6-dioxidohexahydrothieno[3,4-b]pyrazin-1(2H)-yl)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((4aR,7aS)-6,6-dioxidohexahydrothieno[3,4-b]pyrazin-1(2H)-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 40% yield as a yellow solid. m/z(ESI, +ve)=690.8 [M+H]+. ¹H NMR (400 MHz, DMSO-d6) δ 8.04-8.00 (m, 1H),7.82-7.78 (m, 1H), 7.76-7.62 (m, 1H), 6.80 (dd, J=16.0, 8.0 Hz, 1H),6.24 (dd, J=16.0, 4.0 Hz, 1H), 5.82 (d, J=16.0, 4.0 Hz, 1H), 5.35-5.26(m, 1H), 4.88-4.84 (m, 1H), 4.57-4.32 (m, 2H), 4.20-3.76 (m, 5H),3.75-3.42 (m, 5H), 3.38-3.36 (m, 2H), 3.30-3.15 (m, 2H).

Step 1:(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((4aR,7aS)-6,6-dioxidohexahydrothieno[3,4-b]pyrazin-1(2H)-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (4aR,7aS)-octahydrothieno[3,4-b]pyrazine 6,6-dioxide weresubstituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 63% yield as a yellow solid. m/z (ESI, +ve)=636.9 [M+H]+.

Example 1212:(3S)-8-((4aS,7aR)-4-acryloyl-6-(methylsulfonyl)octahydro-1H-pyrrolo[3,4-b]pyrazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-((4aS,7aR)-6-(methylsulfonyl)octahydro-1H-pyrrolo[3,4-b]pyrazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 13% yield as a yellow solid. m/z(ESI, +ve)=719.8 [M+H]+. ¹H NMR (400 MHz, DMSO) δ=7.95 (d, J=8.0 Hz,1H), 7.82-7.71 (m, 2H), 6.84 (s, 1H), 6.22 (dd, J=16.0, 4.0 Hz, 1H),5.79 (d, J=16.0, 4.0 Hz, 1H), 4.97 (s, 1H), 4.65-4.37 (m, 3H), 4.22-3.43(m, 10H), 3.25-3.16 (m, 4H), 3.05-2.84 (m, 3H).

Step 1:(3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-((4aS,7aR)-6-(methylsulfonyl)octahydro-1H-pyrrolo[3,4-b]pyrazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand(4aR,7aS)-6-(methylsulfonyl)octahydro-1H-pyrrolo[3,4-b]pyrazine-methane(1/1) were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 44% yield as a yellow solid. m/z (ESI, +ve)=665.9 [M+H]⁺.

Example 1213:(3S)-8-((4aR,7aS)-4-acryloylhexahydrofuro[3,4-b]pyrazin-1(2H)-yl)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((4aR,7aS)-hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 8% yield as a yellow solid. m/z (ESI,+ve)=642.9 [M+H]+. ¹H NMR (400 MHz, DMSO-d6) δ 7.98-7.62 (m, 3H), 6.81(dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.75 (dd,J=16.0, 4.0 Hz, 1H), 4.87-4.85 (m, 2H), 4.54-4.40 (m, 1H), 4.19-4.16 (m,2H), 4.02-3.97 (m, 3H), 3.86-3.57 (m, 4H), 3.36-3.34 (m, 4H), 3.22-3.14(m, 2H).

Step 1:(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((4aR,7aS)-hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (4aR,7aS)-octahydrofuro[3,4-b]pyrazine-methane (1/1) weresubstituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. m/z (ESI, +ve)=589.1[M+H]+.

Example 1214:(3S)-8-((4aR,7aS)-4-acryloylhexahydrothieno[3,4-b]pyrazin-1(2H)-yl)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((4aR,7aS)-hexahydrothieno[3,4-b]pyrazin-1(2H)-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 4% yield as a yellow solid. m/z (ESI,+ve)=659.0 [M+H]+. ¹H NMR (400 MHz, DMSO-d₆) δ=8.00-7.91 (m, 1H),7.83-7.64 (m, 2H), 6.80-6.76 (m, 1H), 6.20 (dd, J=16.0, 4.0 Hz, 1H),5.76 (dd, J=8.0, 4.0 Hz, 1H), 4.98-4.84 (m, 2H), 4.57-4.52 (m, 1H),3.90-3.67 (m, 4H), 3.58-3.38 (m, 5H), 3.29-3.06 (m, 6H).

Step 1:(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((4aR,7aS)-hexahydrothieno[3,4-b]pyrazin-1(2H)-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (4aR,7aS)-octahydrothieno[3,4-b]pyrazine-methane (1/1) weresubstituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 50% yield as a yellow solid. m/z (ESI, +ve)=605.0 [M+H]+.

Example 1215:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-11-(3-(trifluoromethyl)isothiazol-5-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-11-(3-(trifluoromethyl)isothiazol-5-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 15% yield as a yellow solid. m/z(ESI, +ve)=634.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 8.05(s, 1H), 6.19 (dd, J=16.0 Hz, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz,1H), 5.74 (dd, J=8.0, 4.0 Hz, 1H), 4.70-4.46 (m, 3H), 4.08-4.03 (m, 2H),3.89-3.84 (m, 1H), 3.58-3.35 (m, 5H), 3.31-3.17 (m, 3H), 1.39 (s, 6H).

Step 1: Methyl 4-Amino-2-nitrobenzoate

A mixture of 4-amino-2-nitrobenzoic acid (0.092 mol) in thionyl chloride(1.10 mol) was stirred at 85° C. for 2 hours. The mixture wasconcentrated under reduced pressure to afford a residue that wasdissolved in dichloromethane (200 mL), cooled to 0° C. and treated withmethanol (220 mL). After 30 minutes at 0° C., the volatiles were removedunder reduced pressure and saturated aqueous sodium bicarbonate wasadded over the residue. The resulting suspension was filtered and thefilter cake was washed with water and dried under reduced pressure toafford the title compound in 58% yield as a yellow solid. m/z (ESI,+ve)=197.1 [M+H]+.

Step 2: methyl 4-amino-5-iodo-2-nitrobenzoate

To a solution of methyl 4-amino-2-nitrobenzoate (0.083 mol) in AcOH (125mL) was added N-iodosuccinimide (0.083 mol). The mixture was stirred at100° C. for 16 hours, diluted with water and extracted with ethylacetate three times. The combined organic layers were washed with brine,dried over sodium sulfate, filtered and concentrated under reducedpressure to afford a residue that was triturated with methanol. Thetitle compound was isolated by filtration in 72% yield as a pale brownsolid. m/z (ESI, +ve)=322.9 [M+H]+.

Step 3: Methyl 4-acetamido-5-iodo-2-nitrobenzoate

To a mixture of methyl 4-amino-5-iodo-2-nitrobenzoate (0.047 mol) inacetic acid (150 mL) was added acetic anhydride (0.051 mol). The mixturewas stirred at 100° C. for 2 hours and the volatiles were removed underreduced pressure. The residue was taken up in ethyl acetate and washedwith brine, dried over sodium sulfate and concentrated under reducedpressure to afford a residue that was recrystallized in methanol toafford the title compound in 85% yield as a white solid. m/z (ESI,+ve)=364.9 [M+H]+.

Step 4: Methyl 4-acetamido-2-nitro-5-(trifluoromethyl)benzoate

To a solution of methyl 4-acetamido-5-iodo-2-nitrobenzoate (0.027 mol)in HMPA (50 mL) was added copper (I) iodide (0.038 mol) andtetrabutylammonium iodide (0.014 mol). The mixture was stirred at 50° C.for 30 minutes and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.27mol) was added slowly. The reaction mixture was stirred at 50° C. forone additional hour, quenched with ice-water and diluted with ethylacetate. The insoluble materials were filtered off and the organic layerseparated. The aqueous layer was extracted with ethyl acetate threetimes, the combined organic layers were washed with brine, dried oversodium sulfate, filtered and concentrated under reduced pressure toafford a residue that was purified by silica gel chromatography (0-15%ethyl acetate in hexanes). The title compound was isolated inquantitative yield as a white solid. ¹H NMR (400 MHz, DMSO) δ 10.03 (s,1H), 8.37 (s, 1H), 8.23 (s, 1H), 3.87 (s, 3H), 2.15 (s, 3H).

Step 5: Methyl 4-amino-2-nitro-5-(trifluoromethyl)benzoate

A mixture of methyl 4-acetamido-2-nitro-5-(trifluoromethyl) benzoate (33mmol) in 175 mL of HCl:MeOH (1:2.5 ratio) was stirred at 80° C. for 2hours. The mixture was diluted with water and filtered. The filter cakewas dried under reduced pressure to afford the title compound in 86%yield as a pale green solid. 1H NMR (400 MHz, DMSO) δ 7.90 (s, 1H),7.14-7.12 (m, 3H), 3.76 (s, 3H).

Step 6: Methyl 4-bromo-2-nitro-5-(trifluoromethyl)benzoate

To a mixture of methyl 4-amino-2-nitro-5-(trifluoromethyl) benzoate(0.0585 mol) and CuBr₂ (0.12 mol) in anhydrous acetonitrile (150 mL) at0° C., was added t-BuNO₂ (0.12 mol). The mixture was stirred at 70° C.for 1.5 hours, diluted with water and extracted with ethyl acetate threetimes. The combined organic layers were washed with brine, dried oversodium sulfate, filtered and concentrated under reduced pressure toafford a residue that was purified by silica gel chromatography (0-15%ethyl acetate in hexanes). The title compound was isolated in 94% yieldas a white solid. m/z (ESI, +ve)=328.0 [M+H]+.

Step 7: Methyl 2-amino-4-bromo-5-(trifluoromethyl)benzoate

To a mixture of methyl 4-bromo-2-nitro-5-(trifluoromethyl) benzoate(0.056 mol) in THF/MeOH/H₂O (60 mL:60 mL:60 mL) was added ammoniumchloride (0.113 mol) and iron (0.28 mol). The mixture was stirred at 80°C. for 2 hours, cooled down to room temperature and the solids filteredoff and rinsed with ethyl acetate. Evaporation of volatiles underreduced pressure afforded a residue that was purified by silica gelchromatography (0-17% ethyl acetate in hexanes). The title compound wasisolated in 83% yield as a white solid. m/z (ESI, +ve)=298.0 [M+H]+.

Step 8: Methyl2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoate

A mixture of methyl 2-amino-4-bromo-5-(trifluoromethyl) benzoate (48mmol), bis(pinacolato)diboron (58 mmol), Pd(dppf)Cl₂ (9.6 mmol) andpotassium acetate (0.15 mol) in 1,4-dioxane (150 mL) was stirred at 100°C. for 4 hours. The mixture was cooled down and concentrated to afford aresidue that was purified by silica gel chromatography (25% ethylacetate in hexanes). The title compound was isolated in 90% yield as ayellow solid. m/z (ESI, +ve)=346.2 [M+H]+. ¹H NMR (400 MHz, DMSO) δ 7.96(s, 1H), 7.22 (s, 2H), 7.15 (s, 1H), 3.83 (s, 3H), 1.30 (s, 12H).

Step 9: 5-Iodo-3-(trifluoromethyl)isothiazole

Sodium nitrite (4.47 mmol) was added over a 0° C. solution of3-(trifluoromethyl)isothiazol-5-amine (3.73 mmol) in 50% aqueoussulfuric acid (4 mL). After one hour, KI (4.47 mmol) was added and thereaction mixture heated at 80° C. for one hour. The reaction was cooleddown to room temperature and extracted with diethyl ether three times.The combined organic layers were dried over sodium sulfate and thevolatiles were removed under reduced pressure to afford the titlecompound as a brown oil which was used in the next step without furtherpurification.

Step 10: Methyl2-amino-5-(trifluoromethyl)-4-(3-(trifluoromethyl)isothiazol-5-yl)benzoate

The title compound was prepared analogously to Example 207, step 2,where 5-iodo-3-(trifluoromethyl)isothiazole and methyl2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoatewere substituted in place of 2-bromo-5-fluoro-4-methylpyridine andmethyl 2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate.The title compound was isolated in 21% yield (for the last two steps) asa white solid. m/z (ESI, +ve)=371.0 [M+H]+.

Step 11: Methyl2-amino-3-iodo-5-(trifluoromethyl)-4-(3-(trifluoromethyl)isothiazol-5-yl)benzoate

The title compound was prepared analogously to Example 207, step 3,where methyl2-amino-5-(trifluoromethyl)-4-(3-(trifluoromethyl)isothiazol-5-yl)benzoatewas substituted in place of methyl2-amino-4-(5-fluoropyridin-2-yl)benzoate. The title compound wasisolated in 90% yield as a yellow solid. m/z (ESI, +ve)=496.8 [M+H]+.

Step 12:2-Amino-3-iodo-5-(trifluoromethyl)-4-(3-(trifluoromethyl)isothiazol-5-yl)benzoicacid

The title compound was prepared analogously to Example 207, step 8,where methyl2-amino-3-iodo-5-(trifluoromethyl)-4-(3-(trifluoromethyl)isothiazol-5-yl)benzoatewas substituted in place of methyl2-amino-4-(5-fluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoate. Thetitle compound was isolated in 810% yield as a yellow solid.

m/z (ESI, +ve)=482.8 [M+H]+.

Step 13:8-Iodo-6-(trifluoromethyl)-7-(3-(trifluoromethyl)isothiazol-5-yl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 207, step 9,where2-amino-3-iodo-5-(trifluoromethyl)-4-(3-(trifluoromethyl)isothiazol-5-yl)benzoicacid was substituted in place of2-amino-4-(5-fluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoic acid.The title compound was isolated in 73% yield as a yellow solid. m/z(ESI, +ve)=508.0 [M+H]+

Step 14:(S)-8-((3-Hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)-7-(3-(trifluoromethyl)isothiazol-5-yl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where8-iodo-6-(trifluoromethyl)-7-(3-(trifluoromethyl)isothiazol-5-yl)quinazoline-2,4(1H,3H)-dioneand (S)-3-mercapto-2-methoxypropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 70% yieldas a yellow solid. m/z (ESI, +ve)=502.0 [M+H]+

Step 15:(S)-3-methoxy-10-(trifluoromethyl)-11-(3-(trifluoromethyl)isothiazol-5-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(S)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)-7-(3-(trifluoromethyl)isothiazol-5-yl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 55% yield as a yellow solid. m/z (ESI, +ve)=484.0 [M+H]+.

Step 16:(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-11-(3-(trifluoromethyl)isothiazol-5-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(S)-3-methoxy-10-(trifluoromethyl)-11-(3-(trifluoromethyl)isothiazol-5-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 75% yield as a yellow solid. m/z (ESI, +ve)=580.1 [M+H]+.

Example 1216:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-11-(5-(trifluoromethyl)thiazol-2-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-11-(5-(trifluoromethyl)thiazol-2-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 7% yield as a yellow solid. m/z (ESI,+ve)=634.1 [M+H]+. ¹H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.06 (s,1H), 6.81 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74(dd, J=8.0, 4.0 Hz, 1H), 4.65-4.45 (m, 4H), 4.07-4.04 (m, 2H), 3.89-3.85(m, 1H), 3.54-3.33 (m, 4H), 3.24-3.20 (m, 3H), 1.39 (s, 6H).

Step 1: Methyl2-amino-5-(trifluoromethyl)-4-(5-(trifluoromethyl)thiazol-2-yl)benzoate

The title compound was prepared analogously to Example 207, step 2,where 2-bromo-5-(trifluoromethyl)thiazole and methyl2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoatewere substituted in place of 2-bromo-5-fluoro-4-methylpyridine andmethyl 2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate.The title compound was isolated in 21% yield as a white solid. m/z (ESI,+ve)=370.9 [M+H]+.

Step 2: methyl2-amino-3-iodo-5-(trifluoromethyl)-4-(5-(trifluoromethyl)thiazol-2-yl)benzoate

The title compound was prepared analogously to Example 1207, step 3,where methyl2-amino-5-(trifluoromethyl)-4-(5-(trifluoromethyl)thiazol-2-yl)benzoatewas substituted in place of methyl2-amino-4-(5-fluoropyridin-2-yl)benzoate. The title compound wasisolated in 79% yield as a yellow solid. m/z (ESI, +ve)=496.8 [M+H]+.

Step 3:2-amino-3-iodo-5-(trifluoromethyl)-4-(5-(trifluoromethyl)thiazol-2-yl)benzoicacid

The title compound was prepared analogously to Example 1207, step 8,where methyl2-amino-4-(5-fluoro-4-methylpyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoatewas substituted in place of methyl2-amino-4-(5-fluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoate. Thetitle compound was isolated in 86% yield as a yellow solid. m/z (ESI,+ve)=483.1 [M+H]+

Step 4:8-Iodo-6-(trifluoromethyl)-7-(5-(trifluoromethyl)thiazol-2-yl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 1207, step 9,where2-amino-3-iodo-5-(trifluoromethyl)-4-(5-(trifluoromethyl)thiazol-2-yl)benzoicacid was substituted in place of2-amino-4-(5-fluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoic acid.The title compound was isolated in 55% yield as a brown solid. m/z (ESI,+ve)=507.9 [M+H]+.

Step 5:(S)-8-((3-Hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)-7-(5-(trifluoromethyl)thiazol-2-yl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where8-iodo-6-(trifluoromethyl)-7-(5-(trifluoromethyl)thiazol-2-yl)quinazoline-2,4(1H,3H)-dioneand (S)-3-mercapto-2-methoxypropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 50% yieldas a yellow solid. m/z (ESI, +ve)=502.1 [M+H]+.

Step 6:(S)-3-Methoxy-10-(trifluoromethyl)-11-(5-(trifluoromethyl)thiazol-2-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where(S)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)-7-(5-(trifluoromethyl)thiazol-2-yl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 41% yield as a yellow solid. m/z (ESI, +ve)=484.0 [M+H]+.

Step 7:(S)-8-((3S,5R)-3,5-Dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-11-(5-(trifluoromethyl)thiazol-2-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(S)-3-methoxy-10-(trifluoromethyl)-11-(5-(trifluoromethyl)thiazol-2-yl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 43% yield as a yellow solid. m/z (ESI, +ve)=580.1 [M+H]+.

Example 1217:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(fluoromethoxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(fluoromethoxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 9% yield as a yellow solid. m/z (ESI,+ve)=595.2 [M+H]+.

Step 1: tert-Butyl(2S,6R)-4-((S)-3-(fluoromethoxy)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

Sodium hydride (0.47 mmol) was added over a 0° C. solution of tert-butyl(2S,6R)-4-((S)-11-(4-fluorophenyl)-3-hydroxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(0.16 mmol) in THF (2 mL) and after 15 minutes the cooling bath wasremoved and the reaction was stirred at room temperature for another 15additional minutes. The reaction mixture was cooled again to 0° C. and asolution offluoromethyl-(2-methoxy-1-methoxycarbonyl-2-oxo-ethyl)-phenyl-sulfonium(0.39 mmol) in 500 mL of THF was added slowly. After one hour thereaction was quenched by addition of water and ethyl acetate. Theorganic layer was separated and the aqueous layer extracted three timeswith ethyl acetate. The combined organic layers were dried over sodiumsulfate and concentrated. The resulting residue was purified by silicagel chromatography (20-80% ethyl acetate in hexanes) to afford the titlecompound in 65% yield as a pale yellow solid. m/z (ESI, +ve)=641.2[M+H]+.

Step 2:(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(fluoromethoxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2S,6R)-4-((S)-3-(fluoromethoxy)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.m/z (ESI, +ve)=541.2 [M+H]+.

Example 1218:(3S)-11-(5-Chloro-2,4-difluorophenyl)-8-((3S,5R)-4-(2-fluoroacryloyl)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 418 where(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of10-(2,4-difluorophenyl)-7-(7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 33% yield as a yellow solid. m/z(ESI, +ve)=647.1 [M+H]+. ¹H NMR (400 MHz, DMSO-d6) δ=8.03 (s, 1H),7.82-7.70 (m, 2H), 5.34-5.29 (m, 1H), 5.23 (dd, J=32.0, 4.0 Hz, 1H),4.53-4.41 (m, 3H), 4.89-4.02 (m, 2H), 3.88-3.84 (m, 1H), 3.43-3.34 (m,5H), 3.33-3.28 (m, 2H), 3.22-3.15 (m, 1H), 1.52-1.36 (m, 6H).

Example 1219:(3S)-11-(5-Chloro-2,4-difluorophenyl)-8-(4-(2-fluoroacryloyl)piperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 418 where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of10-(2,4-difluorophenyl)-7-(7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 30% yield as a yellow solid. m/z(ESI, +ve)=619.0 [M+H]+. ¹H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H),7.80-7.75 (m, 2H), 5.35-5.31 (m, 1H), 5.29 (dd, J=64.0, 4.0 Hz, 1H),4.50-4.48 (m, 1H), 3.95-3.70 (m, 9H), 3.55-3.36 (m, 3H), 3.31-3.12 (m,3H).

Example 1220:(3S)-11-(2,4-Difluorophenyl)-8-((3S,5R)-4-(2-fluoroacryloyl)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 418 where(3S)-11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of10-(2,4-difluorophenyl)-7-(7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 34% yield as a yellow solid. m/z(ESI, +ve)=613.2 [M+H]+. ¹H NMR (400 MHz, DMSO-d6) δ=8.03 (s, 1H),7.49-7.35 (m, 2H), 7.30-7.23 (m, 1H), 5.33-5.29 (m, 1H), 5.22 (dd,J=32.0, 4.0 Hz, 1H), 4.52-4.41 (m, 3H), 4.08-4.04 (m, 2H), 3.87-3.81 (m,1H), 3.40-3.33 (m, 6H), 3.32-3.31 (m, 1H), 3.21-3.09 (m, 1H), 1.50-1.38(m, 6H).

Example 1221:(3S)-11-(2,4-Difluorophenyl)-8-(4-(2-fluoroacryloyl)piperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 418 where(3S)-11-(2,4-difluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of10-(2,4-difluorophenyl)-7-(7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 33% yield as a yellow solid. m/z(ESI, +ve)=585.2 [M+H]+. ¹H NMR (400 MHz, DMSO-d6) δ=7.86 (s, 1H),7.47-7.35 (m, 2H), 7.27-7.19 (m, 1H), 5.34-5.29 (m, 1H), 5.27 (dd, J=64,4 Hz, 1H), 4.50-4.42 (m, 1H), 3.88-3.76 (m, 6H), 3.34-3.30 (m, 8H),3.19-3.07 (m, 1H).

Example 1222:(S)-8-((3S,5R)-4-(2-Fluoroacryloyl)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 418 where(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of10-(2,4-difluorophenyl)-7-(7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 33% yield as a yellow solid. m/z(ESI, +ve)=595.2 [M+H]+. ¹H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H),7.41-7.22 (m, 4H), 5.33-5.29 (m, 1H), 5.23 (dd, J=28.0, 4.0 Hz, 1H),4.56-4.39 (m, 3H), 4.14-4.02 (m, 2H), 3.84-3.78 (m, 1H), 3.43-3.34 (m,7H), 3.16-3.04 (m, 1H), 1.58-1.24 (m, 6H).

Example 1223:(S)-8-(4-(2-Fluoroacryloyl)piperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 418 where(S)-11-(4-fluorophenyl)-3-methoxy-8-(piperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of10-(2,4-difluorophenyl)-7-(7-oxo-3,9-diazabicyclo[3.3.1]nonan-3-yl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 40% yield as a yellow solid. m/z(ESI, +ve)=567.0 [M+H]+. ¹H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H),7.42-7.22 (m, 4H), 5.35-5.31 (m, 1H), 5.29 (dd, J=64.0 Hz, 4.0 Hz, 1H),4.54-4.50 (m, 1H), 3.96-3.62 (m, 9H), 3.41-3.34 (m, 5H), 3.14-3.07 (m,1H).

Example 1224:N—((S)-8-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)methanesulfonamide

To a solution of(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-amino-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(0.020 mmol) in dichloromethane (1 mL) were added triethylamine (0.059mmol) and methanesulfonyl chloride (0.04 mmol) at 0° C. The reactionmixture was stirred at room temperature for 1 hour. The volatiles wereremoved under reduced pressure and the resulting residue purified bypreparative HPLC to afford the title compound in 51% yield as a lightyellow solid. m/z (ESI, +ve)=640.0 [M+H]+. ¹H NMR (400 MHz, DMSO-d₆) δ8.04 (s, 1H), 7.35 (m, 4H), 6.82 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd,J=16.0, 4.0 Hz, 1H), 5.75 (dd, J=8.0, 4.0 Hz, 1H), 4.86-4.33 (m, 6H),4.15-3.90 (m, 3H), 3.73-3.56 (m, 1H), 3.27-3.15 (m, 2H), 3.01 (s, 3H),1.40 (s, 6H).

Example 1225:(3S)-8-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-11-(3,5-difluoropyridin-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(3,5-difluoropyridin-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 23% yield as a yellow solid. m/z(ESI, +ve)=596.2 [M+H]+. 1H NMR (400 MHz, DMSO) δ 8.73 (s, 1H),8.24-8.18 (m, 1H), 8.08-8.07 (m, 1H), 6.81 (dd, J=16.0, 8.0 Hz, 1H),6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=8.0, 4.0 Hz, 1H), 4.65-4.55(m, 2H), 4.50-4.43 (m, 2H), 4.09-4.03 (m, 2H), 3.87-3.85 (m, 1H),3.65-3.35 (m, 3H), 3.32-3.08 (m, 4H), 1.50-1.35 (m, 6H).

Step 1: Methyl2-amino-4-(3,5-difluoropyridin-2-yl)-5-(trifluoromethyl)benzoate

The title compound was prepared analogously to Example 1207, step 2,where 2-bromo-3,5-difluoropyridine and methyl2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoatewere substituted in place of 2-bromo-5-fluoropyridine and methyl2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. Thetitle compound was isolated in 72% yield as a yellow solid. m/z (ESI,+ve)=333.1 [M+H]+.

Step 2: Methyl2-amino-4-(3,5-difluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoate

The title compound was prepared analogously to Example 1207, step 7,where methyl2-amino-4-(3,5-difluoropyridin-2-yl)-5-(trifluoromethyl)benzoate wassubstituted in place of methyl2-amino-4-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)benzoate. The titlecompound was isolated in 73% yield as a yellow solid. m/z (ESI,+ve)=459.0 [M+H]+.

Step 3:2-Amino-4-(3,5-difluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoicacid

The title compound was prepared analogously to Example 1207, step 8,where methyl2-amino-4-(3,5-difluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoatewas substituted in place of methyl2-amino-4-(5-fluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoate. Thetitle compound was isolated in 96% yield as a yellow solid. m/z (ESI,+ve)=444.9 [M+H]+.

Step 4:7-(3,5-Difluoropyridin-2-yl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 1207, step 9,where2-amino-4-(3,5-difluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoicacid was substituted in place of2-amino-4-(5-fluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoic acid.The title compound was isolated in 36% yield as a yellow solid. m/z(ESI, +ve)=470.0 [M+H]+

Step 5:7-(3,5-Difluoropyridin-2-yl)-8-(((S)-3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(3,5-difluoropyridin-2-yl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-3-mercapto-2-methoxypropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 75% yieldas a yellow solid. m/z (ESI, +ve)=464.0 [M+H]+.

Step 6:(3S)-11-(3,5-Difluoropyridin-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(3,5-difluoropyridin-2-yl)-8-(((S)-3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.m/z (ESI, +ve)=446.0 [M+H]+.

Step 7:(3S)-11-(3,5-Difluoropyridin-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(3,5-difluoropyridin-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 67% yield (last two steps) as a yellow solid. m/z (ESI,+ve)=542.2 [M+H]+.

Example 1226:2-((3S)-8-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-11-yl)-5-fluorobenzonitrile

The title compound was prepared analogously to Example 84 where2-((3S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinolin-11-yl)-5-fluorobenzonitrilewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 45% yield as a yellow solid. m/z(ESI, +ve)=602.2 [M+H]+. ¹H NMR (400 MHz, DMSO) δ 8.17-8.06 (m, 2H),7.83-7.76 (m, 1H), 7.65-7.53 (m, 1H), 6.81 (dd, J=16.0, 8.0 Hz, 1H),6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=8.0, 4.0 Hz, 1H), 4.64-4.37(m, 3H), 4.11-4.07 (m, 2H), 3.90-3.86 (m, 1H), 3.56-3.43 (m, 1H),3.39-3.33 (m, 4H), 3.33-3.25 (m, 2H), 3.23-3.11 (m, 1H), 1.40 (s, 6H).

Step 1: Methyl5-amino-2′-cyano-4′-fluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate

The title compound was prepared analogously to Example 1207, step 2,where 2-bromo-5-fluorobenzonitrile and methyl2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoatewere substituted in place of 2-bromo-5-fluoropyridine and methyl2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. Thetitle compound was isolated in 77% yield as a white solid. m/z (ESI,+ve)=339.0 [M+H]+.

Step 2: Methyl3-amino-2′-cyano-4′-fluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate

The title compound was prepared analogously to Example 1207, step 7,where methyl5-amino-2′-cyano-4′-fluoro-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylatewas substituted in place of methyl2-amino-4-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)benzoate. The titlecompound was isolated in 94% yield as a white solid. m/z (ESI,+ve)=465.0 [M+H]+.

Step 3:3-Amino-2′-cyano-4′-fluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylicacid

The title compound was prepared analogously to Example 1207, step 8,where methyl3-amino-2′-cyano-4′-fluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylatewas substituted in place of methyl2-amino-4-(5-fluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoate. Thetitle compound was isolated in 95% yield as a white solid. m/z (ESI,+ve)=451.0 [M+H]+.

Step 4:5-Fluoro-2-(8-iodo-2,4-dioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)benzonitrile

The title compound was prepared analogously to Example 1207, step 9,where3-amino-2′-cyano-4′-fluoro-2-iodo-6-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylicacid was substituted in place of2-amino-4-(5-fluoropyridin-2-yl)-3-iodo-5-(trifluoromethyl)benzoic acid.The title compound was isolated in 50% yield as a yellow solid. m/z(ESI, +ve)=475.9 [M+H]+

Step 5:5-Fluoro-2-(8-(((S)-3-hydroxy-2-methoxypropyl)thio)-2,4-dioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)benzonitrile

The title compound was synthesized analogously to example 100, step 9where5-fluoro-2-(8-iodo-2,4-dioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)benzonitrileand (S)-3-mercapto-2-methoxypropan-1-ol were substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 82% yieldas a white solid. m/z (ESI, +ve)=470.0 [M+H]+.

Step 6:5-Fluoro-2-((3S)-3-methoxy-6,8-dioxo-10-(trifluoromethyl)-3,4,7,8-tetrahydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-11-yl)benzonitrile

The title compound was prepared analogously to Example 100, step 10where5-fluoro-2-(8-(((S)-3-hydroxy-2-methoxypropyl)thio)-2,4-dioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)benzonitrilewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 91% yield as a yellow solid. m/z (ESI, +ve)=452.0 [M+H]+.

Step 7:2-((3S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-11-yl)-5-fluorobenzonitrile

The title compound was prepared analogously to Example 100, step 21where5-fluoro-2-((3S)-3-methoxy-6,8-dioxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H,8H-712-[1,4]thiazepino[2,3,4-ij]quinazolin-11-yl)benzonitrileand (2S,6R)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 83% yield as a yellow solid. m/z (ESI, +ve)=548.1 [M+H]+.

Example 1227:8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(2,4-difluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 5% yield as a yellow solid. m/z (ESI,+ve)=565.2 [M+H]+. ¹H NMR (400 MHz, MeOD) δ 8.45 (s, 1H), 8.06 (s, 1H),7.24-7.16 (m, 1H), 7.05-6.97 (m, 1H), 6.74 (dd, J=16.7, 10.7 Hz, 1H),6.19 (dd, J=16.7, 2.0 Hz, 1H), 5.70 (dd, J=10.6, 2.0 Hz, 1H), 4.69-4.49(m, 3H), 4.14 (d, J=13.5 Hz, 2H), 3.38-3.24 (m, 3H), 2.18-2.00 (m, 2H),1.47-1.08 (m, 6H).

Step 1: tert-butyl(2S,6R)-4-(11-(2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where11-(2,4-difluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate weresubstituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 22% yield as a yellow solid. m/z (ESI, +ve)=611.2 [M+H]+.

Step 2:11-(2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2S,6R)-4-(11-(2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated as a yellow solid and used in the nextstep without further purification. m/z (ESI, +ve)=511.2 [M+H]+.

Example 1228:(S)-8-((3S,5R)-4-(acryloyl-d3)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

Oxalyl chloride (0.19 mmol) was added over a 0° C. solution ofacrylic-2,3,3-d3 acid and two drops of DMF in dichloromethane (0.4 mL).After 10 minutes the mixture was stirred at room temperature for 1 hour,cooled down to 0° C. and added to a freshly prepared 0° C. solution of(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(0.09 mmol) and diisopropylethylamine (0.35 mmol) in 0.6 mL of THF.After 10 minutes, the reaction was quenched with water and extractedwith ethyl acetate, dried over sodium sulfate and concentrated to afforda residue that was purified by HPLC to afford the title compound in 57%yield as a yellow solid. m/z (ESI, +ve)=580.2 [M+H]+. ¹H NMR (400 MHz,MeOD) δ 8.03 (s, 1H), 7.21-7.18 (m, 2H), 7.14-7.10 (m, 2H), 4.56 (m,3H), 4.17 (m, 2H), 3.83 (bs, 1H), 3.35 (m, 5H), 2.98 (dd, J=15, 5.2 Hz,1H), 1.40 (m, 6H).

Example 229:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(methoxy-d3)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(methoxy-d3)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 38% yield as a yellow solid. m/z(ESI, +ve)=580.2 [M+H]+. ¹H NMR (400 MHz, MeOD) δ 8.03 (s, 1H),7.21-7.18 (m, 2H), 7.14-7.10 (m, 2H), 6.74 (dd, J=16.7, 10.6 Hz), 6.19(dd, J=16.7, 2.0 HZ, 1H), 5.71 (dd, J=10.6, 2.0 Hz, 1H), 4.57 (dd,J=13.9, 3.9 Hz, 2H), 4.17 (m, 2H), 3.84 (m, 1H), 3.34 (m, 2H), 2.98 (dd,J=15.0, 5.3 Hz, 1H), 1.41 (m, 6H).

Step 1: tert-butyl(2S,6R)-4-((S)-11-(4-fluorophenyl)-3-(methoxy-d3)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

NaH (0.33 mmol) was added over a 0° C. solution of tert-butyl(2S,6R)-4-((S)-11-(4-fluorophenyl)-3-hydroxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(0.16 mmol) in THF (2 mL). After 15 minutes, iodomethane-d3 was addedand the reaction was stirred for 30 additional minutes, quenched withwater and extracted with ethyl acetate three times. The combined organiclayers were dried over sodium sulfate, filtered and concentrated toafford a residue that was purified by HPLC. The title compound wasisolated in quantitative yield as a white solid. m/z (ESI, +ve)=626.2[M+H]+.

Step 2:(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(methoxy-d3)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2S,6R)-4-((S)-11-(4-fluorophenyl)-3-(methoxy-d3)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in quantitative yield as a yellow solid.m/z (ESI, +ve)=526.2 [M+H]+.

Examples 1230 and 1231:(3S,11R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-((5-methylisoxazol-3-yl)oxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-oneand(3S,11S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-((5-methylisoxazol-3-yl)oxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compounds were prepared analogously to Example 84 where(3S,11R)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-((5-methylisoxazol-3-yl)oxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-oneand(3S,11S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-((5-methylisoxazol-3-yl)oxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewere substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one,respectively. The title compounds were isolated in 16% and 26% yield,respectively, as a yellow solids. Example 1230: m/z (ESI, +ve)=696.2[M+H]+; 1H NMR (400 MHz, MeOD) δ 8.07 (s, 1H), 7.43 (m, 1H), 7.25 (m,1H), 6.75 (dd, J=16.7, 2.0 Hz, 1H), 6.20 (d, J=16.7, 2.0 Hz, 1H), 5.71(dd, J=10.6, 2.0 Hz, 1H), 5.49 (d, J=2.0 Hz, 1H), 4.57 (m, 3H), 4.25 (m,2H), 4.10-3.88 (m, 4H), 3.45-3.34 (m, 2H), 2.15 (d, J=3.6 Hz, 3H), 1.47(d, J=4 Hz, 3H), 1.30 (d, J=4 Hz, 3H).

Example 1231: m/z (ESI, +ve)=696.2 [M+H]+; 1H NMR (400 MHz, MeOD) δ 8.07(s, 1H), 7.43-7.39 (m, 1H), 7.31-7.25 (m, 1H), 6.75 (dd, J=16.7, 2.0 Hz,1H), 6.20 (d, J=16.7, 2.0 Hz, 1H), 5.71 (dd, J=10.6, 2.0 Hz, 1H), 5.49(d, J=2.0 Hz, 1H), 4.60-4.48 (m, 3H), 4.25 (m, 2H), 4.10-3.88 (m, 4H),3.45-3.34 (m, 2H), 2.15 (s, 3H), 1.47 (d, J=4 Hz, 3H), 1.30 (d, J=4 Hz,3H).

Step 1: tert-butyl(2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-3-((5-methylisoxazol-3-yl)oxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

A solution of triphenylphosphine (0.45 mmol) and DIAD (0.45 mmol) in THF(5 mL) was stirred at 0° C. for 5 minutes. A solution of5-methylisoxazol-3-ol (0.45 mmol) and tert-butyl(2S,6R)-4-((3R)-11-(5-chloro-2,4-difluorophenyl)-3-hydroxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(0.15 mmol) was added and the resulting mixture was stirred at roomtemperature for 3 hours. The reaction was diluted with ethyl acetate andwashed with brine. The organic layer was dried over sodium sulfate,filtered and concentrated to afford a residue that was purified bypreparative thin layer chromatography (10% methanol in ethyl acetate).The title compound was isolated in 27% yield as a white solid. m/z (ESI,+ve)=742.2 [M+H]+.

Step 2:(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-((5-methylisoxazol-3-yl)oxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-3-((5-methylisoxazol-3-yl)oxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.m/z (ESI, +ve)=642.1 [M+H]+.

Example 1232:2-(((S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)oxy)-N,N-dimethylacetamide

The title compound was prepared analogously to Example 84 where2-(((S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)oxy)-N,N-dimethylacetamidewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 59% yield as a yellow solid. m/z(ESI, +ve)=648.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H),7.28-7.07 (m, 4H), 6.55 (dd, J=16.7, 10.4 Hz, 1H), 6.34 (dd, J=16.7, 1.9Hz, 1H), 5.70 (dd, J=10.3, 1.9 Hz, 1H), 4.80-4.02 (m, 8H), 3.34-3.12 (m,3H), 2.90 (s, 3H), 2.68 (s, 3H), 1.66-1.20 (m, 6H). Step 1: tert-butyl(2S,6R)-4-((S)-3-(2-(dimethylamino)-2-oxoethoxy)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate.

Sodium hydride (0.08 mmol) was added over a 0° C. solution of tert-butyl(2S,6R)-4-((S)-11-(4-fluorophenyl)-3-hydroxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(0.07 mmol) in THF (2 mL). After 15 minutes,2-bromo-N,N-dimethylacetamide (0.08 mmol) was added and the mixturestirred at room temperature for 45 minutes. The reaction was quenched byaddition of water, extracted with ethyl acetate and the organic layerdried over sodium sulfate, filtered and concentrated to afford a residuethat was purified by preparative HPLC. The title compound was isolatedas a white solid in 71% yield. m/z (ESI, +ve)=694.2 [M+H]+.

Step 2:2-(((S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)oxy)-N,N-dimethylacetamide

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2S,6R)-4-((S)-3-(2-(dimethylamino)-2-oxoethoxy)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in quantitative yield as a yellow solid.m/z (ESI, +ve)=594.2 [M+H]+.

Example 1233:2-(((S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)oxy)acetamide

The title compound was prepared analogously to Example 84 where2-(((S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)oxy)acetamidewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 51% yield as a yellow solid. m/z(ESI, +ve)=620.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.11(q, J=8.9, 6.8 Hz, 3H), 6.55 (dd, J=16.6, 10.4 Hz, 1H), 6.34 (dd,J=16.6, 1.9 Hz, 1H), 5.71 (dd, J=10.4, 1.9 Hz, 1H), 5.54 (s, 1H),5.37-3.58 (m, 9H), 3.50-2.67 (m, 4H), 1.40 (d, J=6.1 Hz, 8H).

Step 1: tert-butyl(2S,6R)-4-((S)-3-(2-amino-2-oxoethoxy)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 1232, step 1,where 2-bromoacetamide was substituted in place of2-bromo-N,N-dimethylacetamide. The title compound was isolated in 44%yield as a yellow solid. m/z (ESI, +ve)=666.2 [M+H]+.

Step 2:2-(((S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)oxy)acetamide

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2S,6R)-4-((S)-3-(2-amino-2-oxoethoxy)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in quantitative yield as a yellow solid.m/z (ESI, +ve)=566.2 [M+H]+.

Example 1234:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(pyridin-4-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-4-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 9% yield as a white solid. m/z (ESI,+ve)=692.1 (M+H)+. ¹H NMR (400 MHz, dmso) δ 8.46-8.34 (m, 2H), 8.08 (s,1H), 7.86-7.67 (m, 2H), 7.04-7.01 (m, 2H), 6.81 (dd, J=16.0, 8.0 Hz,1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.75 (dd, J=8.0, 4.0 Hz, 1H),5.34-5.26 (m, 1H), 4.62-4.58 (m, 2H), 4.46-3.97 (m, 4H), 3.49-3.45 (m,1H), 3.40-3.36 (m, 2H), 3.26-3.22 (m, 1H), 1.42-1.37 (m, 6H).

Step 1:(S)-4-((1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-yl)oxy)pyridine

DIAD (0.02 mol) was added over a 0° C. solution of(R)-1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-ol (0.01mol) and PPh3 (0.02 mol) in THF (75 mL). The mixture was allowed toreach room temperature slowly and after 16 hours the volatiles wereremoved under reduced pressure to afford a residue that was purified bysilica gel chromatography. The title compound was isolated in 64% yieldas a colorless oil. m/z (ESI, +ve)=666.3 (M+H)+.

Step 2:(S)-3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-4-yloxy)propane-1-thiol

Triethylsilane (0.02 mol) was added over a 0° C. solution of(S)-4-((1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-yl)oxy)pyridine(0.01 mol) in dichloromethane:trifluoroacetic acid (45 mL:15 mL). After30 minutes, the reaction was quenched with water and extracted withdichloromethane five times. The combined organic layers were dried oversodium sulfate, filtered and concentrated to afford a residue that waspurified by chromatography in silica gel. The title compound wasisolated as a colorless oil in 78% yield. m/z (ESI, +ve)=424.2 [M+H]+.

Step 3:8-(((S)-3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-4-yloxy)propyl)thio)-7-(5-chloro-2,4-difluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(5-chloro-2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand(S)-3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-4-yloxy)propane-1-thiolwere substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 33% yieldas a yellow solid. m/z (ESI, +ve)=798.0 [M+H]+.

Step 4:7-(5-chloro-2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-(pyridin-4-yloxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

TBAF (3 mmol) was added over a solution of8-(((S)-3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-4-yloxy)propyl)thio)-7-(5-chloro-2,4-difluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(1 mmol) in THF (10 mL). After 3 hours, the reaction was quenched withwater and extracted with ethyl acetate three times. The combined organiclayers were dried over sodium sulfate, filtered and concentrated toafford a residue that was purified by silica gel chromatography. Thetitle compound was isolated in 71% yield as a yellow solid. m/z (ESI,+ve)=560.0 [M+H]+.

Step 5:(3S)-11-(5-chloro-2,4-difluorophenyl)-3-(pyridin-4-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(5-chloro-2,4-difluorophenyl)-8-(((S)-3-hydroxy-2-(pyridin-4-yloxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 51% yield as a yellow solid. m/z (ESI, +ve)=542.0 [M+H]+.

Step 6:(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-4-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-(pyridin-4-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2S,6R)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 42% yield as a yellow solid. m/z (ESI, +ve)=638 [M+H]+.

Example 1235:2-((3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-11-yl)-5-fluorobenzamide

The title compound was prepared analogously to Example 100, step 21where5-fluoro-2-((3S)-3-methoxy-6,8-dioxo-10-(trifluoromethyl)-3,4,7,8-tetrahydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-11-yl)benzamideand 1-((2S,6R)-2,6-dimethylpiperazin-1-yl)prop-2-en-1-one weresubstituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 10% yield as a yellow solid. m/z (ESI, +ve)=620.2 [M+H]+. ¹HNMR (400 MHz, DMSO-d₆) δ 8.0-7.96 (m, 1H), 7.84-7.76 (m, 1H), 7.72-7.62(m, 1H), 7.50-7.46 (m, 1H), 7.29-7.23 (m, 2H), 6.82 (dd, J=16.0, 8.0 Hz,1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.74 (dd, J=8.0, 4.0 Hz, 1H),4.74-4.36 (m, 4H), 4.07-4.04 (m, 2H), 3.86-3.82 (m, 1H), 3.32-3.26 (m,6H), 3.09-3.06 (m, 1H), 1.40 (s, 6H).

Step 1:5-fluoro-2-((3S)-3-methoxy-6,8-dioxo-10-(trifluoromethyl)-3,4,7,8-tetrahydro-2H,6H-[14]thiazepino[2,3,4-ij]quinazolin-11-yl)benzamide

An aqueous 0.6M solution of potassium hydroxide (2 mL) was added over asolution of5-fluoro-2-((3S)-3-methoxy-6,8-dioxo-10-(trifluoromethyl)-3,4,7,8-tetrahydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-11-yl)benzonitrile(0.44 mmol) in ethanol (20 mL). The mixture was heated at 80° C. for 16hours, cooled down to room temperature and the pH adjusted to 3 byaddition of a 3M solution of HCl. The resulting mixture was extractedwith ethyl acetate three times and the combined organic layers driedover sodium sulfate, filtered and concentrated to afford the titlecompound as a yellow solid in 43% yield. m/z (ESI, +ve)=492.0 [M+H]+.

Example 1236:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(2-(diethylamino)ethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-(diethylamino)ethoxy)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 38% yield as a yellow solid. m/z(ESI, +ve)=714.2 [M+H]+. ¹H NMR (400 MHz, DMSO-d₆) δ=9.08 (s, 1H), 8.07(s, 1H), 7.82-7.78 (m, 1H), 6.81 (dd, J=16.0, 8.0 Hz, 1H), 6.20 (dd,J=16.0, 4.0 Hz, 1H), 5.75 (dd, J=8.0, 4.0 Hz, 1H), 4.73-4.42 (m, 3H),4.12-4.05 (m, 3H), 3.85-3.81 (m, 1H), 3.36-3.32 (m, 6H), 3.19-3.15 (m,4H), 1.40-1.30 (m, 6H), 1.19-1.17 (m, 6H).

Step 1:(S)-2-((1-((tert-butyldimethylsilyl)oxy)-3-(tritylthio)propan-2-yl)oxy)-N,N-diethylacetamide

A solution of(S)-1-((tert-butyldimethylsilyl)oxy)-3-(tritylthio)propan-2-ol (24.1mmol) in THF (30 mL) was added over a suspension of NaH in THF (20 mL)at 0° C. After 30 minutes, a solution of 2-chloro-N,N′-diethylacetamide(28.7 mmol) in DMF (50 mL) was added and the reaction stirred at roomtemperature for 1 hour. The reaction was quenched with water, extractedwith ethyl acetate and washed with brine, dried over sodium sulfate andfiltered. Evaporation of volatiles afforded a residue that was purifiedby silica gel chromatography (ethyl acetate with 0.10% NH4OH) to affordthe title compound in 80% yield as a yellow oil. m/z (ESI, +ve)=600.3[M+H]+.

Step 2:(S)-2-((1-((tert-butyldimethylsilyl)oxy)-3-(tritylthio)propan-2-yl)oxy)-N,N-diethylethan-1-amine

LiAlH₄ (26.3 mmol) was added over a 0° C. solution of(S)-2-((1-((tert-butyldimethylsilyl)oxy)-3-(tritylthio)propan-2-yl)oxy)-N,N-diethylacetamide(19 mmol) in THF (80 mL). The mixture was stirred at 60° C. for 1 hour,cooled down to room temperature and quenched with sodium sulfatedecahydrate. The solids were filtered and the resulting solutionconcentrated to afford the title compound as a yellow oil in 84% yield.m/z (ESI, +ve)=564.4 [M+H]+.

Step 3: (S)-2-(2-(diethylamino)ethoxy)-3-mercaptopropan-1-ol

Triethylsilane (47.6 mmol) was added over a solution of(S)-2-((1-((tert-butyldimethylsilyl)oxy)-3-(tritylthio)propan-2-yl)oxy)-N,N-diethylethan-1-amine(16 mmol) in dichloromethane:trifluoroacetic acid (60 mL:15 mL). After20 minutes water was added and the mixture extracted withdichloromethane. Evaporation of volatiles afforded the title compound asa yellow oil in quantitative yield. m/z (ESI, +ve)=208.2 [M+H]+.

Step 4:7-(5-chloro-2,4-difluorophenyl)-8-(((S)-2-(2-(diethylamino)ethoxy)-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(5-chloro-2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-2-(2-(diethylamino)ethoxy)-3-mercaptopropan-1-ol weresubstituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 74% yieldas a white solid. m/z (ESI, +ve)=582.1 [M+H]+.

Step 5:(3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-(diethylamino)ethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(5-chloro-2,4-difluorophenyl)-8-(((S)-2-(2-(diethylamino)ethoxy)-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 97% yield as a yellow solid. m/z (ESI, +ve)=564.0 [M+H]+.

Step 6: tert-butyl(2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-(diethylamino)ethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where(3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-(diethylamino)ethoxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate weresubstituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 50% yield as a yellow solid. m/z (ESI, +ve)=760.2 [M+H]+.

Step 7:(3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-(diethylamino)ethoxy)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-3-(2-(diethylamino)ethoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in quantitative yield as a brown oil.m/z (ESI, +ve)=660.2 [M+H]+.

Example 1237:8′-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11′-(5-chloro-2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[cyclopropane-1,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one

The title compound was prepared analogously to Example 100, step 21where11′-(5-chloro-2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[cyclopropane-1,3′-[1,4]thiazepino[2,3,4-ij]quinazoline]-6′,8′(7′H)-dioneand 1-((2R,6S)-2,6-dimethylpiperazin-1-yl)prop-2-en-1-one weresubstituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 37% yield as a yellow solid. m/z (ESI, +ve)=625.2 [M+H]+. ¹HNMR (400 MHz, DMSO) δ 8.06 (s, 1H), 7.80-7.76 (m, 2H), 6.82 (dd, J=16.0,8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.75 (dd, J=8.0, 4.0 Hz,1H), 4.62-4.56 (m, 3H), 4.27-4.23 (m, 1H), 4.20-4.0 (m, 2H), 3.34-3.20(m, 4H), 1.44-1.37 (m, 6H), 0.90-0.55 (m, 4H).

Step 1: (1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanol

To a mixture of cyclopropane-1,1-diyldimethanol (0.15 mol) and imidazole(0.37 mol) in DMF (150 mL) was added TBDPSCl (0.15 mol) and the reactionmixture was stirred at room temperature for 16 hours. The reaction wasquenched by addition of water and the mixture extracted with ethylacetate, dried over sodium sulfate and filtered. Evaporation ofvolatiles afforded a residue that was purified by silica gelchromatography (0-5% ethyl acetate in hexanes). The title compound wasisolated in 47% yield as a colorless oil. m/z (ESI, +ve)=363.1 (M+H)⁺.

Step 2: S-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)ethanethioate

To a 0° C. solution of PPh₃ (5.8 mmol) in THF (15 mL) was added DIAD(5.8 mmol) and the mixture was stirred 10 minutes. A solution of(1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanol (2.9 mmol)and ethanethioic S-acid (5.8 mmol) in THF (10 mL) was added and thereaction stirred at 0° C. for an addition hour. Evaporation of volatilesand purification of the resulting residue by reverse phasechromatography afforded the title compound in 86% yield as a colorlessoil. m/z (ESI, +ve)=421.1 [M+Na]⁺.

Step 3:(1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanethiol

Hydrazine hydrate (19.8 mmol) was added over a solution ofS-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)ethanethioate (1.25 mmol) in methanol (10 mL). The reaction was stirredat room temperature for one hour and quenched with a mixture of waterand ethyl acetate. The organic layer was separated, dried over sodiumsulfate, filtered and concentrated to afford a residue that was purifiedby chromatography in silica gel (hexanes). The title compound wasisolated in 85% yield as a colorless oil. m/z (ESI, +ve)=379.2 [M+Na]+.

Step 4:8-(((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)thio)-7-(5-chloro-2,4-difluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(5-chloro-2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanethiolwere substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 68% yieldas a white solid. m/z (ESI, +ve)=753.0 [M+H]+.

Step 5:7-(5-chloro-2,4-difluorophenyl)-8-(((1-(hydroxymethyl)cyclopropyl)methyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

TBAF (1.84 mL) was added over a solution of8-(((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)thio)-7-(5-chloro-2,4-difluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(0.61 mmol) in THF (20 mL). After three hours the reaction wasconcentrated under reduced pressure and the crude material purified byreverse phase chromatography. The title compound was isolated in 93%yield as a white solid. m/z (ESI, +ve)=493.0 [M+H]+.

Step 6:11′-(5-chloro-2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[cyclopropane-1,3′-[1,4]thiazepino[2,3,4-ij]quinazoline]-6′,8′(7′H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(5-chloro-2,4-difluorophenyl)-8-(((1-(hydroxymethyl)cyclopropyl)methyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 87% yield as a yellow solid. m/z (ESI, +ve)=475.0 [M+H]+.

Example 238:8′-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11′-(5-chloro-2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[cyclobutane-1,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one

The title compound was prepared analogously to Example 84 where11′-(5-chloro-2,4-difluorophenyl)-8′-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[cyclobutane-1,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 30% yield as a yellow solid. m/z(ESI, +ve)=639.2 [M+H]+. ¹H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H),7.81-7.66 (m, 2H), 6.82 (dd, J=16.0, 8.0 Hz, 1H), 6.20 (dd, J=16.0, 4.0Hz, 1H), 5.75 (dd, J=8.0, 4.0 Hz, 1H), 4.08-4.04 (m, 2H), 3.42-3.36 (m,3H), 3.35-3.31 (m, 2H), 3.28-3.18 (m, 3H), 2.02-1.67 (m, 6H), 1.56-1.05(m, 6H).

Step 1: Cyclobutane-1,1-diyldimethanol

To a solution of cyclobutane-1,1-dicarboxylic acid (0.069 mol) in THF(100 mL) at 0° C. was added LiAlH₄ (0.28 mol). The resulting mixture wasstirred at room temperature for 4 hours, quenched with Na₂SO₄.10H₂O (100g) and filtered. The filtrate was dried over sodium sulfate andconcentrated under reduced pressure to afford the title compound ascolorless oil in 51% yield. m/z (ESI, +ve)=139.0 [M+Na]⁺.

Step 2: (1-((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanol

To a mixture of cyclobutane-1,1-diyldimethanol (0.037 mol) and imidazole(0.074 mol) in DMF (60 mL) was added TBDPSCl (0.030 mol). The reactionmixture was stirred at room temperature for 4 hours. The reactionmixture was quenched with water, extracted with ethyl acetate threetimes and the combined organic layers were washed with water, dried oversodium sulfate and filtered. The filtrate was concentrated under reducedpressure to afford a residue that was purified by silica gel columnchromatography (10% ethyl acetate in hexanes) to afford the titlecompound in 36% yield as colorless oil. m/z (ESI, +ve)=377 [M+Na]⁺.

Step 3: S-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methyl)ethanethioate

To a 0° C. solution of triphenylphosphine (48 mmol) in THF (100 mL) wasadded DIAD (60 mmol) and after 20 minutes a solution of(1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanol (24 mmol)and ethanethioic S-acid (72 mmol) in THF (10 mL) was added. The reactionwas stirred for another 40 minutes and quenched with water and extractedwith ethyl acetate three times. The combined organic layers were washedwith water, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated under reduced pressure to afford a residue that waspurified by silica gel column chromatography (10% ethyl acetate inhexanes) to afford the title compound in 59% yield as a colorless oil.m/z (ESI, +ve)=413.0 [M+H]+.

Step 4: (1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanethiol

To a 0° C. mixture ofS-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methyl)ethanethioate (2.4 mmol) in MeOH (20 mL):H₂O (2 mL) was added K₂CO₃(11.9 mmol). After one hour, the reaction mixture was diluted with water(10 mL) and extracted with ethyl acetate three times. The combinedorganic layers were washed with water, dried over Na₂SO₄ and filtered.The filtrate was concentrated under reduced pressure to afford a residuethat was purified by silica gel column chromatography (10% ethyl acetatein hexanes) to afford the title compound in 50% yield as colorless oil.m/z (ESI, +ve)=393.1 [M+H]+.

Step 5:8-(((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methyl)thio)-7-(5-chloro-2,4-difluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(5-chloro-2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanethiolwere substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 72% yieldas a yellow solid. m/z (ESI, +ve)=767.1 [M+Na]+.

Step 6:7-(5-chloro-2,4-difluorophenyl)-8-(((1-(hydroxymethyl)cyclobutyl)methyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

A 1M solution of TBAF in THF (20 mL) was added over a solution of8-(((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)thio)-7-(5-chloro-2,4-difluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(1.60 mmol) in THF (10 mL). After 16 hours the reaction was concentratedunder reduced pressure and the crude material purified by reverse phasechromatography. The title compound was isolated in 62% yield as a yellowsolid. m/z (ESI, +ve)=507.0 [M+H]+.

Step 7:11′-(5-chloro-2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[cyclobutane-1,3′-[1,4]thiazepino[2,3,4-ij]quinazoline]-6′,8′(7′H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(5-chloro-2,4-difluorophenyl)-8-(((1-(hydroxymethyl)cyclobutyl)methyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 83% yield as a yellow solid. m/z (ESI, +ve)=489.0 [M+H]+.

Step 8:11′-(5-chloro-2,4-difluorophenyl)-8′-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[cyclobutane-1,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one

The title compound was prepared analogously to Example 100, step 21where11′-(5-chloro-2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[cyclobutane-1,3′-[1,4]thiazepino[2,3,4-ij]quinazoline]-6′,8′(7′H)-dioneand (2S,6R)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in quantitative yield as a yellow solid. m/z (ESI, +ve)=585.1[M+H]+.

Example 1239:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-bromo-2,4-difluorophenyl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(5-bromo-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 50% yield as a yellow solid. m/z(ESI, +ve)=673.0 [M+H]+. ¹H NMR (400 MHz, DMSO-d₆) δ 8.04-8.03 (m, 1H),7.85-7.71 (m, 2H), 6.81 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0Hz, 1H), 5.74 (dd, J=8.0, 4.0 Hz, 1H), 4.61-4.57 (m, 2H), 4.51-4.48 (m,1H), 4.08-4.04 (m, 2H), 3.90-3.83 (m, 1H), 3.37-3.35 (m, 2H), 3.32-3.17(m, 6H), 1.43-1.37 (m, 6H).

Step 1:2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

To a solution of 5-bromo-2,4-difluoroaniline (7.2 mmol) in DMF (30 mL)were added 1,1′-bis(diphenylphosphino)ferrocenepalladiumdichloride (1.4mmol), bis(pinacolato)diboron (11 mmol) and potassium acetate (21.6mmol). The reaction mixture was stirred at 85° C. for 2 hours. Themixture was cooled to room temperature and filtered. The filtrate wasconcentrated to afford a residue that was purified by silica gelchromatography (0-10% ethyl acetate in hexanes) to afford the titlecompound in 65% yield as a yellow oil. m/z (ESI, +ve)=256.1 [M+H]+.

Step 2: tert-butyl(2S,6R)-4-((3S)-11-(5-amino-2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

To a mixture of tert-butyl(2S,6R)-4-((S)-11-chloro-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(0.53 mmol), Ruphos-Pd G2 (0.053 mmol) and potassium phosphate (1.6mmol) in dioxane/H₂O (16 mL/4 mL) was added2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(1.60 mmol). The reaction mixture was stirred at 80° C. for 2 hours,cooled to room temperature and filtered. The filtrate was concentratedto afford a residue that was purified by reverse phase chromatography(5-75% acetonitrile in water with 0.1% TFA) to afford the title compoundin 52% yield as a yellow solid. m/z (ESI, +ve)=656.2 [M+H]+.

Step 3: tert-butyl(2S,6R)-4-((3S)-11-(5-bromo-2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

To a mixture of tert-butyl(2S,6R)-4-((3S)-11-(5-amino-2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(0.30 mmol) in acetonitrile (10 mL) were added tert-butyl nitrite (0.61mmol) and cupric bromide (0.61 mmol). The mixture was stirred at roomtemperature for 2 hours and concentrated under reduced pressure. Thecrude was purified by reverse phase chromatography (5-75% acetonitrilein water with 0.1% TFA) to afford the title compound in 82% yield as awhite solid. m/z (ESI, +ve)=720.1 [M+H]+.

Step 4:(3S)-11-(5-bromo-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2S,6R)-4-((3S)-11-(5-bromo-2,4-difluorophenyl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 99% yield as a yellow solid. m/z(ESI, +ve)=620.0 [M+H]+.

Example 1240:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-((2,2,2-trifluoroethyl)amino)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

To a 0° C. solution of(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-amino-11-(5-chloro-2,4-difluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(0.065 mmol) in DMF (1 mL) were added N,N-diisopropylethylamine (0.13mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.13 mmol).The reaction mixture was stirred at room temperature for 16 hours. Thesolvent was removed under reduced pressure and the resulting crudematerial was purified by preparative HPLC to afford the title compoundas a yellow solid in 7% yield. m/z (ESI, +ve)=696.1 [M+H]+. ¹H NMR (400MHz, methanol-d4) δ 8.46 (s, 1H), 8.06 (s, 1H), 7.80-7.75 (m, 1H), 6.81(dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0 Hz, 1H), 5.75 (dd,J=8.0, 4.0 Hz, 1H), 4.75-4.38 (m, 4H), 4.16-3.98 (m, 2H), 3.19-2.93 (m,7H), 1.51-1.32 (m, 6H).

Step 1: (S)-(2-azido-3-(tritylthio)propoxy)(tert-butyl)diphenylsilane

To a 0° C. solution oftert-butyl[(2R)-2-hydroxy-3-[(triphenylmethyl)sulfanyl]propoxy]diphenylsilane(74.7 mmol) and PPh3 (749 mmol) in THF (300 mL) was slowly added DEAD(149 mmol). After 20 minutes, DPPA (97.1 mmol) was added to the solutionand stirred at room temperature 16 hours. The solution was quenched withwater and concentrated to afford a residue that was purified by silicagel chromatography (0-10% ethyl acetate in hexanes) to afford the titlecompound in 93% yield as colorless oil.

Step 2: (S)-2-azido-3-((tert-butyldiphenylsilyl)oxy)propane-1-thiol

To a solution of[(2S)-2-azido-3-[(triphenylmethyl)sulfanyl]propoxy](tert-butyl)diphenylsilane(48.9 mmol) in dichloromethane/TFA (150 mL/35 mL) was addedtriethylsilane (147 mmol) and the solution was stirred for 20 minutes.The reaction was diluted with water and extracted with dichloromethanethree times. The combined organic layers were washed with brine anddried over sodium sulfate. The organic layer was concentrated to afforda residue that was purified by silica gel chromatography (0-8% methanolin dichloromethane) to afford the title compound in 50% yield as yellowoil.

Step 3: tert-butyl((2S)-1-((tert-butyldiphenylsilyl)oxy)-3-((7-(5-chloro-2,4-difluorophenyl)-2,4-dioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-8-yl)thio)propan-2-yl)carbamate

The title compound was synthesized analogously to example 100, step 9where7-(5-chloro-2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand (S)-2-azido-3-((tert-butyldiphenylsilyl)oxy)propane-1-thiol weresubstituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 50% yieldas a yellow solid. m/z (ESI, +ve)=721.1 [M+H]+.

Step 4: tert-butyl((2S)-1-((7-(5-chloro-2,4-difluorophenyl)-2,4-dioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-8-yl)thio)-3-hydroxypropan-2-yl)carbamate

To a solution of tert-butyl((2S)-1-((tert-butyldiphenylsilyl)oxy)-3-((7-(5-chloro-2,4-difluorophenyl)-2,4-dioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-8-yl)thio)propan-2-yl)carbamate(9.50 mmol) in THF (50 mL) was added 1M solution of TBAF in THF (14.2mmol). The solution was stirred at room temperature for 30 minutes,concentrated and purified by reversed phase chromatography (40-70%acetonitrile in water with 0.1% TFA) to afford the title compound in 93%yield as a white solid. m/z (ESI, +ve)=526.0 [M+H]+.

Step 5: tert-butyl((3S)-11-(5-chloro-2,4-difluorophenyl)-6,8-dioxo-10-(trifluoromethyl)-3,4,7,8-tetrahydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)carbamate

The title compound was prepared analogously to Example 100, step 10where tert-butyl((2S)-1-((7-(5-chloro-2,4-difluorophenyl)-2,4-dioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-8-yl)thio)-3-hydroxypropan-2-yl)carbamatewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 83% yield as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ=11.97 (s,2H), 8.13-8.10 (m, 1H), 7.81-7.64 (m, 2H), 4.25 (m, 2H), 3.20 (m, 2H),2.94 (m, 1H), 1.40-1.38 (m, 9H).

Step 6: tert-butyl((3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)carbamate

To a 0° C. solution of tert-butyl((3S)-11-(5-chloro-2,4-difluorophenyl)-6,8-dioxo-10-(trifluoromethyl)-3,4,7,8-tetrahydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)carbamate(0.98 mmol) in acetonitrile (10 mL) were added potassium carbonate (13.3mmol) and tosyl chloride (8.8 mmol). The reaction mixture was stirred atroom temperature for 16 hours and1-((2R,6S)-2,6-dimethylpiperazin-1-yl)prop-2-en-1-one (8.85 mmol) inacetonitrile (10 mL) was added. After 1 hour the suspension was filteredthrough a pad of celite and the filtrate was concentrated under reducedpressure to afford a residue that was purified by C18 chromatographyusing 30-70% acetonitrile in water (with 0.05% aq NH₃) as eluent. Thetitle compound was isolated in 12% yield as a white solid. m/z (ESI,+ve)=736.1 [M+Na]+.

Step 7:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-amino-11-(5-chloro-2,4-difluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

To a 0° C. solution of tert-butyl((3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)carbamate(0.056 mmol) in dichloromethane (1 mL) was added TFA (0.3 mL). Thereaction mixture was stirred at room temperature for 2 hours andconcentrated under reduced pressure to afford the title compound in 98%yield as a yellow solid. m/z (ESI, +ve)=614.0 [M+H]+.

Example 1241:8′-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11′-(5-chloro-2,4-difluorophenyl)-1-(2,2,2-trifluoroethyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[azetidine-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one

The title compound was prepared analogously to Example 84 where11′-(5-chloro-2,4-difluorophenyl)-8′-((3S,5R)-3,5-dimethylpiperazin-1-yl)-1-(2,2,2-trifluoroethyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[azetidine-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 29% yield as a yellow solid. m/z(ESI, +ve)=722.0 [M+H]+. ¹H NMR (400 MHz, DMSO) δ=8.11 (s, 1H),7.87-7.72 (m, 2H), 6.87 (dd, J=16.0, 8.0 Hz, 1H), 6.25 (dd, J=16.0, 4.0Hz, 1H), 5.80 (dd, J=8.0, 4.0 Hz, 1H), 4.66-4.62 (m, 2H), 4.17-4.07 (m,2H), 3.47-3.42 (m, 4H), 3.37-3.19 (m, 8H), 1.60-1.35 (m, 6H).

Step 1: benzyl 2-oxa-6-azaspiro[3.3]heptane-6-carboxylate

To a 0° C. mixture of 2-oxa-6-azaspiro[3.3]heptane (0.10 mol) andtriethylamine (0.30 mol) in THF (100 mL) was added Cbz-Cl (0.15 mol).The resulting solution was warmed to room temperature and stirred for 16hours, quenched with water, extracted with ethyl acetate, washed withbrine and dried over Na₂SO₄ to afford after evaporation of volatilesunder reduced pressure a residue that was purified by silica gel columnchromatography (0-80% ethyl acetate in hexanes). The title compound wasisolated in 52% yield as a colorless oil. m/z (ESI, +ve)=234.1 [M+H]+.

Step 2: benzyl 3-(bromomethyl)-3-(hydroxymethyl)azetidine-1-carboxylate

To a solution of benzyl 2-oxa-6-azaspiro[3.3]heptane-6-carboxylate (0.11mol) in dichloromethane (150 mL) was added HBr (40% in water, 15 mL).The reaction mixture was stirred for 2 hours and the pH of the mixturewas adjusted to 6-7 by the addition of aqueous saturated NaHCO₃ (200 mL)and extracted with dichloromethane three times. The combined organiclayers were washed with brine, dried over Na₂SO₄ and concentrated toafford a residue that was purified by silica gel column chromatography(0-10% methanol in dichloromethane) to afford the title compound in 95%yield as a yellow oil. m/z (ESI, +ve)=314.0 [M+H]+.

Step 3: benzyl3-(hydroxymethyl)-3-(mercaptomethyl)azetidine-1-carboxylate

To a mixture of benzyl3-(bromomethyl)-3-(hydroxymethyl)azetidine-1-carboxylate (0.64 mol) inMeOH (200 mL) was added NaSH (0.32 mol). The reaction mixture wasstirred for 16 hours and concentrated under reduced pressure to afford aresidue that was purified by silica gel column chromatography (0-10%methanol in dichloromethane) to afford the title compound in 76% yieldas a yellow oil. m/z (ESI, +ve)=314.0 [M+H]+.

Step 4: benzyl3-(((7-(5-chloro-2,4-difluorophenyl)-2,4-dioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-8-yl)thio)methyl)-3-(hydroxymethyl)azetidine-1-carboxylate

The title compound was synthesized analogously to example 100, step 9where7-(5-chloro-2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand benzyl 3-(hydroxymethyl)-3-(mercaptomethyl)azetidine-1-carboxylatewere substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 66% yieldas a yellow solid. m/z (ESI, +ve)=642.0 [M+H]+.

Step 5: benzyl11′-(5-chloro-2,4-difluorophenyl)-6′,8′-dioxo-10′-(trifluoromethyl)-7′,8′-dihydro-2′H,4′H,6′H-spiro[azetidine-3,3′-[1,4]thiazepino[2,3,4-ij]quinazoline]-1-carboxylate

The title compound was prepared analogously to Example 100, step 10where benzyl3-(((7-(5-chloro-2,4-difluorophenyl)-2,4-dioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-8-yl)thio)methyl)-3-(hydroxymethyl)azetidine-1-carboxylatewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 90% yield as a yellow solid. m/z (ESI, +ve)=624.0 [M+H]+.

Step 6: benzyl8′-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-11′-(5-chloro-2,4-difluorophenyl)-6′-oxo-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[azetidine-3,3′-[1,4]thiazepino[2,3,4-ij]quinazoline]-1-carboxylate

The title compound was prepared analogously to Example 100, step 21where benzyl11′-(5-chloro-2,4-difluorophenyl)-6′,8′-dioxo-10′-(trifluoromethyl)-7′,8′-dihydro-2′H,4′H,6′H-spiro[azetidine-3,3′-[1,4]thiazepino[2,3,4-ij]quinazoline]-1-carboxylateand tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate weresubstituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 49% yield as a yellow solid. m/z (ESI, +ve)=820.0 [M+H]+.

Step 7: tert-butyl(2S,6R)-4-(11′-(5-chloro-2,4-difluorophenyl)-6′-oxo-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[azetidine-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-8′-yl)-2,6-dimethylpiperazine-1-carboxylate

A mixture of benzyl8′-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-11′-(5-chloro-2,4-difluorophenyl)-6′-oxo-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[azetidine-3,3′-[1,4]thiazepino[2,3,4-ij]quinazoline]-1-carboxylate(0.37 mmol) and 10% Pd on carbon (100 mg) in isopropyl alcohol (5 mL)was hydrogenated for 16 hours. The solids were filtered out and thefiltrate was concentrated under reduced pressure to afford a residuethat was purified by reversed phase chromatography (30-50% acetonitrilein water with 0.10% TFA) to afford the title compound in 36% yield as alight yellow solid. m/z (ESI, +ve)=686.2 [M+H]+.

Step 8: tert-butyl(2S,6R)-4-(11′-(5-chloro-2,4-difluorophenyl)-6′-oxo-1-(2,2,2-trifluoroethyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[azetidine-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-8′-yl)-2,6-dimethylpiperazine-1-carboxylate

To a mixture of tert-butyl(2S,6R)-4-(11′-(5-chloro-2,4-difluorophenyl)-6′-oxo-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[azetidine-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-8′-yl)-2,6-dimethylpiperazine-1-carboxylate(0.64 mmol) in DMF (5 mL) were added diisopropylethylamine (1.92 mmol)and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.64 mmol). Thereaction mixture was stirred at room temperature for 2 hours and thevolatiles removed under reduced pressure to afford a residue that waspurified by reversed phase chromatography (40-80% acetonitrile in waterwith 0.10% TFA). The title compound was isolated in 53% yield as a lightyellow solid. m/z (ESI, +ve)=768.0 [M+H]+.

Step 9:11′-(5-chloro-2,4-difluorophenyl)-8′-((3S,5R)-3,5-dimethylpiperazin-1-yl)-1-(2,2,2-trifluoroethyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[azetidine-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2S,6R)-4-(11′-(5-chloro-2,4-difluorophenyl)-6′-oxo-1-(2,2,2-trifluoroethyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[azetidine-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-8′-yl)-2,6-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in 97% yield as a yellow solid. m/z(ESI, +ve)=668.0 [M+H]+.

Example 1242:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(6-amino-3,5-difluoropyridin-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 84 where(3S)-11-(6-amino-3,5-difluoropyridin-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 33% yield as a white solid. m/z (ESI,+ve)=611.2 [M+H]+. ¹H NMR (400 MHz, DMSO) δ=8.02 (s, 1H), 7.88-7.67 (m,1H), 6.81 (dd, J=16.0, 8.0 Hz, 1H), 6.58-6.34 (m, 2H), 6.19 (dd, J=16.0,4.0 Hz, 1H), 5.74 (dd, J=8.0, 4.0 Hz, 1H), 4.88-4.23 (m, 4H), 4.16-3.96(m, 2H), 3.92-3.78 (m, 1H), 3.37-3.32 (m, 3H), 3.31-3.01 (m, 4H), 1.39(s, 6H).

Step 1: 2-(6-amino-3,5-difluoropyridin-2-yl)isoindoline-1,3-dione

To a solution of 3,5-difluoropyridine-2,6-diamine (0.031 mol) in aceticacid (50 mL) was added isobenzofuran-1,3-dione (0.031 mol). The reactionmixture was stirred at 100° C. for 3 hours and quenched with water. Theresulting suspension was filtered through a pad of celite and the filtercake was washed with water. The filtrate was concentrated under reducedpressure to afford the title compound in 82% yield as a light yellowsolid. m/z (ESI, +ve)=276.0 [M+H]+.

Step 2: 2-(6-bromo-3,5-difluoropyridin-2-yl)isoindoline-1,3-dione

To a 0° C. solution of2-(6-amino-3,5-difluoropyridin-2-yl)isoindoline-1,3-dione (0.011 mol) inacetonitrile (20 mL) were added CuBr₂ (0.0218 mol) and t-BuONO (0.0218mol). The reaction mixture was stirred at room temperature for 2 hours.The solvent was removed and the residue taken up in water. The mixturewas extracted with ethylacetate, washed with brine, dried over sodiumsulfate and concentrated to afford a residue that was purified by silicagel chromatography (0-10% ethyl acetate in hexanes) to afford the titlecompound in 76% yield as a white solid. m/z (ESI, +ve)=341.0 [M+H]+.

Step 3: 6-bromo-3,5-difluoropyridin-2-amine

2-(6-bromo-3,5-difluoropyridin-2-yl)isoindoline-1,3-dione (1.47 mmol)was dissolved in a solution of NH₃ in MeOH (5 mL) and stirred at roomtemperature for 1 hour. The solvent was removed to afford a residue thatwas purified by silica gel chromatograph (0-10% ethyl acetate inhexanes) to afford 6-bromo-3,5-difluoropyridin-2-amine (84%) as a whitesolid. m/z (ESI, +ve)=211.0 [M+H]+.

Step 4: 6-bromo-3,5-difluoro-N,N-bis(4-methoxybenzyl)pyridin-2-amine

To a 0° C. solution of 6-bromo-3,5-difluoropyridin-2-amine (4.8 mmol) inDMA (10 ml) was added NaH (10.5 mmol). The resulting suspension wasstirred for 30 min at 0° C., and then 1-(chloromethyl)-4-methoxybenzene(1.8 g, 0.0115 mol) was added. The reaction was stirred for 1 hour atroom temperature and quenched by the addition of saturated aqueousNH₄Cl. The mixture was extracted with ethyl acetate, washed with water,dried over sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure to afford a residue that was purified by silicagel chromatography (10% ethyl acetate in hexanes) to afford the titlecompound in 97% yield as a white solid. m/z (ESI, +ve)=449.0 [M+H]+.

Step 5:3,5-difluoro-N,N-bis(4-methoxybenzyl)-6-(tributylstannyl)pyridin-2-amine

To a mixture of6-bromo-3,5-difluoro-N,N-bis(4-methoxybenzyl)pyridin-2-amine (4.7 mmol),LiCl (23.5 mmol), PCy₃ (0.023.5 mmol) and Pd₂(dba)₃ (0.4 mmol) in1,4-dioxane (20 mL) was added hexabutylditin (7.0 mmol). The resultingmixture was stirred at 80° C. for 3 hours, the solids were filtered outand the filtrate concentrated under reduced pressure to afford a residuethat was purified by silica gel chromatography (10% ethyl acetate inhexanes). The title compound was isolated in 87% yield as a yellow oil.m/z (ESI, +ve)=661.2 [M+H]+.

Step 6: tert-butyl(2S,6R)-4-((3S)-11-(6-(bis(4-methoxybenzyl)amino)-3,5-difluoropyridin-2-yl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

To a mixture of tert-butyl(2S,6R)-4-((S)-11-chloro-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(2.7 mmol) and3,5-difluoro-N,N-bis(4-methoxybenzyl)-6-(tributylstannyl)pyridin-2-amine(3.2 mmol) in 1,4-dioxane (20 mL) were added CsF (5.9 mol) andbis(tri-tert-butylphosphine)palladium(0) (0.2 mmol). The resultingmixture was stirred at 110° C. for 16 hours, the solid was filtered outand the filtrate was concentrated under reduced pressure to afford aresidue that was purified by reversed phase chromatography (85%acetonitrile in water with 0.05% TFA) to afford the title compound in23% yield as a yellow solid. m/z (ESI, +ve)=897.2 [M+H]+.

Step 7:(3S)-11-(6-amino-3,5-difluoropyridin-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 102, step 4,where tert-butyl(2S,6R)-4-((3S)-11-(6-(bis(4-methoxybenzyl)amino)-3,5-difluoropyridin-2-yl)-3-methoxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(3S)-4-(10-chloro-11-(2,4-difluorophenyl)-6-oxo-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-3-methylpiperazine-1-carboxylate.The title compound was isolated in quantitative yield as a yellow solid.m/z (ESI, +ve)=557.1 [M+H]+.

Example 1243:8′-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11′-(5-chloro-2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[cyclobutane-1,3′-[1,4]thiazepino[2,3,4-ij]quinazoline]-3,6′-dione

The title compound was prepared analogously to Example 84 where11′-(5-chloro-2,4-difluorophenyl)-8′-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[cyclobutane-1,3′-[1,4]thiazepino[2,3,4-ij]quinazoline]-3,6′-dionewas substituted in place of9-chloro-10-(2,4-difluorophenyl)-7-(3,3-dioxido-3-thia-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one.The title compound was isolated in 24% yield as a yellow solid. m/z(ESI, +ve)=653.1 [M+H]+. ¹H NMR (400 MHz, DMSO-d₆) δ 8.07 (s, 1H), 7.79(t, J=9.2 Hz, 2H), 6.82 (dd, J=16.0, 8.0 Hz, 1H), 6.19 (dd, J=16.0, 4.0Hz, 1H), 5.75 (dd, J=16.0, 4.0 Hz, 1H), 4.95-4.44 (m, 5H), 4.16-4.08 (m,2H), 3.82-3.41 (m, 3H), 3.31-3.19 (m, 2H), 3.09-2.84 (m, 2H), 1.49-1.24(m, 6H).

Step 1:S-((1-(((tert-butyldiphenylsilyl)oxy)methyl)-3,3-dimethoxycyclobutyl)methyl)ethanethioate

Over a 0° C. solution of PPh₃ (0.019 mol) in THF (50 mL) was added DIAD(0.021 mol) and after 20 minutes(1-(((tert-butyldiphenylsilyl)oxy)methyl)-3,3-dimethoxycyclobutyl)methanol(0.010 mol) and ethanethioic S-acid (28.9 mmol) were added. After 1 hourthe volatiles were removed under reduced pressure and the resultingresidue was purified by reverse phase chromatography (95% acetonitrilein water with 0.1% TFA) to afford the title compound in 90% yield as acolorless oil. m/z (ESI, +ve)=495.1 [M+Na]⁺.

Step 2:(1-(((tert-butyldiphenylsilyl)oxy)methyl)-3,3-dimethoxycyclobutyl)methanethiol

To a mixture ofS-((1-(((tert-butyldiphenylsilyl)oxy)methyl)-3,3-dimethoxycyclobutyl)methyl)ethanethioate (5.81 mmol) in THF (10 mL) and MeOH (10 mL) was addedhydrazine hydrate (116.10 mmol). The reaction mixture was stirred atroom temperature for 1 hour. The reaction mixture was quenched withwater and extracted with ethyl acetate three times. The organic layerswere combined, washed with water (20 mL), dried over Na₂SO₄ andfiltered. The filtrate was concentrated under reduced pressure to affordresidue which was purified by silica gel chromatograph (PE/EA=8/1) toafford(1-(((tert-butyldiphenylsilyl)oxy)methyl)-3,3-dimethoxycyclobutyl)methanethiol(1.8 g, 64%) as colorless oil. m/z (ESI, +ve)=453.1 [M+Na]⁺.

Step 3:8-(((1-(((tert-butyldiphenylsilyl)oxy)methyl)-3,3-dimethoxycyclobutyl)methyl)thio)-7-(5-chloro-2,4-difluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was synthesized analogously to example 100, step 9where7-(5-chloro-2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand(1-(((tert-butyldiphenylsilyl)oxy)methyl)-3,3-dimethoxycyclobutyl)methanethiolwere substituted in place of7-(2,4-difluorophenyl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand 2-mercaptoethan-1-ol. The title compound was isolated in 40% yieldas a white solid. m/z (ESI, +ve)=827.1 [M+Na]⁺.

Step 4:7-(5-chloro-2,4-difluorophenyl)-8-(((1-(hydroxymethyl)-3,3-dimethoxycyclobutyl)methyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

To a solution of8-(((1-(((tert-butyldiphenylsilyl)oxy)methyl)-3,3-dimethoxycyclobutyl)methyl)thio)-7-(5-chloro-2,4-difluorophenyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(1.4 mmol) in THF (15 mL) was added TBAF (2.8 mmol) and the reaction wasstirred at room temperature for 16 hours. The mixture was concentratedunder reduced pressure to afford a residue that was purified by reversedphase chromatography (65% acetonitrile in water with 0.1% TFA) to affordthe title compound in 92% yield as a colorless oil. m/z (ESI, +ve)=567.1[M+H]+.

Step 5:11′-(5-chloro-2,4-difluorophenyl)-3,3-dimethoxy-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[cyclobutane-1,3′-[1,4]thiazepino[2,3,4-ij]quinazoline]-6′,8′(7′H)-dione

The title compound was prepared analogously to Example 100, step 10where7-(5-chloro-2,4-difluorophenyl)-8-(((1-(hydroxymethyl)-3,3-dimethoxycyclobutyl)methyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionein 30% yield as a colorless oil. m/z (ESI, +ve)=549.1 [M+H]⁺.

Step 6:11′-(5-chloro-2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[cyclobutane-1,3′-[1,4]thiazepino[2,3,4-ij]quinazoline]-3,6′,8′(7′H)-trione

To a mixture of11′-(5-chloro-2,4-difluorophenyl)-3,3-dimethoxy-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[cyclobutane-1,3′-[1,4]thiazepino[2,3,4-ij]quinazoline]-6′,8′(7′H)-dione(0.382 mmol) in acetonitrile (5 mL) was added TFA (1 mL). The reactionmixture was stirred at room temperature for 1 hour. And after that timethe volatiles were removed under reduced pressure to afford the titlecompound in 75% yield as an off-white solid. m/z (ESI, +ve)=502.9[M+H]⁺.

Step 7:11′-(5-chloro-2,4-difluorophenyl)-8′-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[cyclobutane-1,3′-[1,4]thiazepino[2,3,4-ij]quinazoline]-3,6′-dione

The title compound was prepared analogously to Example 100, step 21where11′-(5-chloro-2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[cyclobutane-1,3′-[1,4]thiazepino[2,3,4-ij]quinazoline]-3,6′,8′(7′H)-trioneand (2S,6R)-2,6-dimethylpiperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 25% yield as a brown solid. m/z (ESI, +ve)=599.1 [M+H]+.

Example 1301:(3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

The title compound was prepared according to the scheme below.

Step 1:(1S,4S)-5-((R)-oxiran-2-ylmethyl)-2-oxa-5-azabicyclo[2.2.1]heptanes

The solution of (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (38.2 g,147.5 mmol) in acetonitrile (300 mL) was added(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (1) (20.0 g, 147.5 mmol) andpotassium carbonate (61 g, 442.5 mmol) at 0° C. under nitrogenatmosphere. The mixture was stirred under nitrogen atmosphere at roomtemperature for 16 hours. After completion, the mixture was concentratedand the residue was purified by silica gel column withdichloromethane/methanol=20/1 to afford the product (2) (15.0 g, yield:66%) as a yellow oil. MS (ESI) m/z 156.1 [M+H]⁺.

Step 2:(R)-1-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3-mercaptopropan-2-ol(3)

To a mixture of(1S,4S)-5-((R)-oxiran-2-ylmethyl)-2-oxa-5-azabicyclo[2.2.1]heptane (2)(6 g, 38.7 mmol) in tetrahydrofuran (60 mL) were added1,1,1,3,3,3-hexamethyldisilathiane (8.9 g, 50.3 mmol) andtetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 11.6 mL, 11.6mmol) at 0° C. The mixture was stirred at room temperature for 2 hours.After completion, the mixture was poured into water (60 mL), extractedwith ethyl acetate (3×100 mL). The organic phase was washed with brine(200 mL) and dried over anhydrous sodium sulfate. After filtration andconcentration, the residue was purified by silica gel column withdichloromethane/methanol=50/1 to afford(R)-1-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3-mercaptopropan-2-ol(3) (2.6 g, yield: 35%) as a colorless oil. MS (ESI) m/z 190.1 [M+H]+.

Step 3:8-(((R)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-hydroxypropyl)thio)-7-chloro-4-hydroxy-6-(trifluoromethyl)quinazolin-2(1H)-one(4)

To a solution of7-chloro-4-hydroxy-8-iodo-6-(trifluoromethyl)quinazolin-2(1H)-one (4.00g, 9.10 mmol) in dioxane (100 mL) were added potassium carbonate (3.70g, 27.3 mmol),(R)-1-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3-mercaptopropan-2-ol(3) (2.57 g, 13.6 mmol),4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (1.05 g, 1.82 mmol) andtris(dibenzylideneacetone) dipalladium (0.823 g, 0.91 mmol). The mixturewas stirred at 55° C. under nitrogen atmosphere for 8 hours. Aftercompletion, the mixture was diluted with tetrahydrofuran (200 mL) andinsoluble was filtered out. The filtrate was concentrated and theresidue was purified by silica gel column chromatography(dichloromethane/methanol=100/1 to 20/1) to afford8-(((R)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-hydroxypropyl)thio)-7-chloro-4-hydroxy-6-(trifluoromethyl)quinazolin-2(1H)-one(4) (4.00 g, yield: 97%) as a yellow solid. MS (ESI) m/z 452.5 [M+H]⁺.

Step 4:(S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-chloro-7-hydroxy-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5)

To a mixture of8-(((R)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-hydroxypropyl)thio)-7-chloro-4-hydroxy-6-(trifluoromethyl)quinazolin-2(1H)-one(4) (3.50 g, 7.70 mmol) and triphenylphosphine (3.00 g, 11.6 mmol) intetrahydrofuran (50 mL) was added diethyl azodicarboxylate (2.60 g, 15.4mmol) at 0° C. The mixture was stirred at 0° C. for 45 min. Aftercompletion, the mixture was poured into ice-water (200 mL) and extractedwith ethyl acetate (3×200 mL). Concentrated and the residue was purifiedby flash chromatography column (C18, acetonitrile/water=30% to 95%) toafford(S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-chloro-7-hydroxy-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5) (3.14 g, yield: 70%) as a white solid. MS (ESI) m/z 434.4 [M+H]⁺

Step 5: (2S,6R)-tert-butyl4-((S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-chloro-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6)

To a mixture of(S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-chloro-7-hydroxy-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5) (700 mg, 1.60 mmol) and potassium carbonate (2.20 g, 16.0 mmol) inacetonitrile (20 mL) was added 4-methylbenzenesulfonic anhydride (782mg, 2.40 mmol) at 25° C. The mixture was stirred at 25° C. for 3 hours.(2R,6S)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (684 mg, 3.20mmol) was added into the reaction solution. The reaction mixture wasstirred at 25° C. for 1 hour. After completion, the mixture was pouredinto ice-water (50 mL) and extracted with ethyl acetate (3×50 mL). Themixture was concentrated and the residue was purified by flashchromatography column (C18, acetonitrile/water=20% to 95%) to afford(2S,6R)-tert-butyl4-((S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-chloro-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6) (800 mg, yield: 80%) as a yellow solid. MS (ESI) m/z 630.6 [M+H]⁺.

Step 6: (2S,6R)-tert-butyl4-((3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(7)

To a solution of (2S,6R)-tert-butyl4-((S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-chloro-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6) (300 mg, 0.476 mmol) in 1,4-dioxane (10 mL) and water (2 mL) wereadded tripotassium phosphate (404 mg, 1.90 mmol),(2,4-difluorophenyl)boronic acid (602 mg, 3.81 mmol), andchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(74 mg, 0.095 mmol). The mixture was stirred at 85° C. under nitrogenatmosphere for 4 hours. After completion, the mixture was diluted withtetrahydrofuran (50 mL) and insoluble was filtered out. The filtrate wasconcentrated and the residue was purified by silica gel columnchromatography (dichloromethane/methanol=100/1 to 30/1) to afford(2S,6R)-tert-butyl4-((3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(7) (252 mg, yield: 75%) as a yellow solid. MS (ESI) m/z 708.4 [M+H]⁺.

Step 7:(3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a cooled mixture of (2S,6R)-tert-butyl4-((3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-(2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(7) (252 mg, 0.36 mmol) in dichloromethane (5 mL) was addedtrifluoroacetic acid (1 mL) at 0° C. The reaction solution was stirredat room temperature for 1 hour. After completion, the mixture wasconcentrated. The residue was redissolved in dichloromethane and washedwith saturated NaHCO₃. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel columnchromatography (dichloromethane/methanol=15:1) to afford(3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8) (185 mg, yield: 85%) as a yellow solid. MS (ESI) m/z 608.1 [M+H]+.

Step 8:(3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9)

To a mixture of(3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8) (160 mg, 0.26 mmol) and triethyl amine (40 mg, 0.39 mmol) indichloromethane (5 mL) was added acrylic anhydride (40 mg, 0.31 mmol) at0° C. The mixture was stirred at 0° C. for 1 hour. After completion, themixture was poured into ice-water (50 mL) and extracted with ethylacetate (3×20 mL). The mixture was concentrated and the residue waspurified by preparative high performance liquid chromatography (20% to95% acetonitrile in water) to afford(3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9) (103 mg, yield: 59%) as a white solid. MS (ESI) m/z 662.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.21-7.14 (m, 1H), 7.06-6.93 (m,2H), 6.66-6.59 (m, 1H), 6.43-6.38 (m, 1H), 5.77 (d, J=12.0 Hz, 1H),5.28-5.24 (m, 1H), 4.74-4.60 (m, 2H), 4.43-4.37 (m, 1H), 4.19 (d, J=13.6Hz, 2H), 3.91-3.84 (m, 1H), 3.69-3.31 (m, 5.5H), 2.99-2.85 (m, 4.5H),1.75-1.66 (m, 2H), 1.60-1.58 (m, 3H), 1.49-1.41 (m, 3H).

Example 1309:8′-(4-acryloylpiperazin-1-yl-2,2,3,3,5,5,6,6-d₈)-11′-(5-chloro-2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one

The title compound was prepared according to the scheme below.

Step 1:11′-(5-chloro-2,4-difluorophenyl)-8′-hydroxy-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one(2)

Compound 1 (25 mg, 0.066 mmol, 1 equiv) was dissolved in 1,4-dioxane andH₂O (1.3 mL, 0.3 mL, respectively, 0.04 M). The resulting mixture waspurged with N₂ for 30 min prior to the addition of RuPhos Pd G4 (5.6 mg,0.0066 mmol, 10 mol %), K₃PO₄ (42 mg, 0.20 mmol, 3 equiv), and(5-chloro-2,4-difluorophenyl)boronic acid (63.5 mg, 0.33 mmol, 5 equiv).The microwave vial was fitted with a crimp-top cap, bubbled with N₂ foran additional 5 min, and placed on a heated block at 80° C. Theresulting reaction mixture was homogenous and orange. After 1 h, thevial was removed from the heating block, allowed to cool, and thesolvent was removed by rotary evaporation (95% conversion; determined byLC-MS). The crude material was filtered through a pad of silica gelusing 3% MeOH/DCM (50 mL), and the solvent was removed by rotaryevaporation. The material was used as is in the subsequent step: TLC (3%MeOH/CH₂Cl₂) R_(f)=0.24; LRMS-ESI (m/z) [M−H]⁺ calculated forC₂₀H₁₁ClF₅N₂O₃S 489.01, found 489.1.

Step 2:11′-(5-chloro-2,4-difluorophenyl)-8′-(piperazin-1-yl-2,2,3,3,5,5,6,6-d₈)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one(3)

Compound 2 (32.4 mg, 0.066 mmol, 1 equiv) was dissolved in MeCN (0.5 mL)under a N₂ atmosphere in a 20 dr vial containing 3 Å molecular sieves.1,8-Diazabicyclo[5.4.0]undec-7-ene (19.7 μL, 0.132 mmol, 2 equiv) wasadded by syringe to the reaction mixture followed by PYBOP (52 mg, 0.1mmol, 1.5 equiv) at room temperature. The orange solution was stirredfor 15 minutes, piperazine-2,2,3,3,5,5,6,6-d₈ (18.6 mg, 0.2 mmol, 3equiv) was added at room temperature and the reaction mixture was heatedat 60° C. After 2 hours, additional 1,8-diazabicyclo[5.4.0]undec-7-ene(19.7 μL, 0.132 mmol, 2 equiv) and PYBOP (52 mg, 0.1 mmol, 1.5 equiv)was added and heated at 60° C. for 2.5 h (full conversion by LC-MS).After allowing the reaction mixture to cool to room temperature, thesolvent was removed and the residue was dissolved in MeOH, loaded onto aHyperSep SCX plug, and flushed with MeOH (ca. 30 mL). Next, the desiredproduct was eluted with 1N NH₃ in MeOH (ca. 30 mL) and collected. Thesolvent was removed by rotary evaporation and used as is in thesubsequent step: ¹H NMR (400 MHz, MeOH-d₄) δ 7.94 (s, 1H), 7.48 (t,J=7.8 Hz, 1H), 7.34 (t, J=9.1 Hz, 1H), 4.88-4.54 (m, 2H), 4.43 (dd,J=6.3, 1.7 Hz, 2H), 3.56 (d, J=6.7 Hz, 2H), 3.16 (sextet, J=3.7 Hz, 2H);LRMS-ESI (m/z) [M+H]⁺ calculated for C₂₄H₁₃D₈ClF₅N₄O₂S 567.15, found567.2.

Step 3:8′-(4-acryloylpiperazin-1-yl-2,2,3,3,5,5,6,6-d₈)-11′-(5-chloro-2,4-difluorophenyl)-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one(4)

The acrylation was carried out by using the same procedure described asin other examples. 7.04 mg (yield: 17%) of title compound 4 was obtainedas white solid. ¹H NMR (400 MHz, MeOH-d₄) δ 8.01 (s, 1H), 7.49 (t, J=7.5Hz, 1H), 7.34 (t, J=9.1 Hz, 1H), 6.80 (dd, J=16.8, 10.6 Hz, 1H), 6.27(dd, J=16.8, 2.0 Hz, 1H), 5.80 (dd, J=10.6, 1.9 Hz, 1H), 4.88-4.58 (m,4H), 4.44 (dd, J=6.3, 2.8 Hz, 2H), 3.66-3.47 (m, 2H); LRMS-ESI (m/z)[M+H]⁺ calculated for C₂₇H₁₅D₈ClF₅N₄O₃S 621.16, found 621.2.

Examples 1312 and 1313:(3S,10S)-3-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one (P1) and(3S,10R)-3-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazepino[2,3,4-ij]quinazolin-5-one

The title compound was prepared according to the scheme below.

Step 1: (R)-oxiran-2-ylmethyl)-2-oxa-7-azaspiro[3.5]nonane (2)

A solution of (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (5.9 g, 22.8mmol) in acetonitrile (60 mL) was added 2-oxa-7-azaspiro[3.5]nonaneoxalate (1) (4.5 g, 20.7 mmol) and potassium carbonate (14.3 g, 103.6mmol) at 0° C. under nitrogen atmosphere. The mixture was stirred undernitrogen atmosphere at room temperature for 16 hours. After completion,the mixture was concentrated and the residue was purified by silica gelcolumn with dichloromethane/methanol=20/1 to afford(R)-7-(oxiran-2-ylmethyl)-2-oxa-7-azaspiro[3.5]nonane (2) (3.45 g,yield: 91%) as a brown oil. MS (ESI) m/z 180.1 [M+H]⁺.

Step 2: (R)-1-mercapto-3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propan-2-ol(3)

To a mixture of (R)-7-(oxiran-2-ylmethyl)-2-oxa-7-azaspiro[3.5]nonane(2) (3.74 g, 20.4 mmol) in tetrahydrofuran (70 mL) was added1,1,1,3,3,3-hexamethyldisilathiane (5.45 g, 30.6 mmol) andtetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 6.1 mL, 6.1 mmol)at 0° C. The mixture was stirred at room temperature for 6 hours. Aftercompletion, the mixture was concentrated. The residue was purified bysilica gel column with dichloromethane/methanol=20/1 to afford(R)-1-mercapto-3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propan-2-ol (3) (3.47g, yield: 78%) as a brown oil. MS (ESI) m/z 218.2 [M+H]⁺.

Step 3:(R)-7-chloro-4-hydroxy-8-((2-hydroxy-3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(4)

To a solution of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2 g,4.59 mmol) in dioxane (50 mL) were added potassium carbonate (2.5 g,18.36 mmol),(R)-1-mercapto-3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propan-2-ol (3) (3.2g, 6.88 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (526 g,0.91 mmol) and tris(dibenzylideneacetone) dipalladium (421 mg, 0.46mmol). The mixture was stirred at 50° C. under nitrogen atmosphere for16 hours. After completion, the mixture was concentrated. The residuewas purified by silica gel column with dichloromethane/methanol=20/1 toafford(R)-7-chloro-4-hydroxy-8-((2-hydroxy-3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(4) (2.2 g, yield: 89%) as an orange solid. MS (ESI) m/z 480.9 [M+H]⁺.

Step 4:(S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-chloro-7-hydroxy-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5)

To a mixture of(R)-7-bromo-6-chloro-4-hydroxy-8-((2-hydroxy-3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propyl)thio)quinazolin-2(1H)-one(4) (2.16 g, 4.5 mmol) and triphenylphosphine (1.77 g, 6.75 mmol) intetrahydrofuran (70 mL) was added diethyl azodicarboxylate (1.18 g, 6.75mmol). The mixture was stirred at room temperature for 2 hours. Aftercompletion, the mixture was poured into ice-water (100 mL) and extractedwith ethyl acetate (3×100 mL). The mixture was concentrated and theresidue was purified by silica gel column withdichloromethane/methanol=50/1 to afford(S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-chloro-7-hydroxy-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5) (1.8 g, yield: 87%) as a light yellow solid. MS (ESI) m/z 462.3[M+H]⁺.

Step 5: (2R,5S)-tert-butyl4-((S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-bromo-9-chloro-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(6)

To a mixture of(S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-bromo-9-chloro-7-hydroxy-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5) (0.7 g, 1.52 mmol) and potassium carbonate (2.1 g, 15.2 mmol) inacetonitrile (60 mL) was added 4-methylbenzenesulfonic anhydride (992mg, 3.04 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min andat 30° C. for 1 hour. After completion, (2R,5S)-tert-butyl2,5-dimethylpiperazine-1-carboxylate (977 mg, 4.56 mmol) was added intothe reaction solution. The reaction mixture was stirred at 0° C. for 1hour. After completion, the mixture was poured into ice-water (300 mL)and extracted with ethyl acetate (3×200 mL). The mixture wasconcentrated and the residue was purified by flash chromatography column(C18, acetonitrile/water=20% to 95%) to afford (2R,5S)-tert-butyl4-((S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-bromo-9-chloro-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(6) (650 mg, yield: 65%) as a pale-white solid. MS (ESI) m/z 658.2[M+H]⁺.

Step 6: (2R,5S)-tert-butyl4-((3S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-(5-chloro-2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(7)

To a mixture of (2R,5S)-tert-butyl4-((S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-bromo-9-chloro-5-oxo-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(6) (300 mg, 0.46 mmol) and tripotassium orthophosphate (297 mg, 1.4mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.05mmol) and (5-chloro-2,4-difluorophenyl)boronic acid (631 mg, 2.3 mmol).The mixture was stirred at 85° C. for 2 hours. After completion, themixture was purified by silica gel column withdichloromethane/methanol=50/1 to afford (2R,5S)-tert-butyl4-((3S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-(5-chloro-2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(7) (260 mg, crude) as a light yellow oil. MS (ESI) m/z 770.2 [M+H]⁺.

Step 7:(3S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-(5-chloro-2,4-difluorophenyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a mixture of (2R,5S)-tert-butyl4-((3S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-(5-chloro-2,4-difluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,5-dimethylpiperazine-1-carboxylate(7) (260 mg, 0.33 mmol) in dichloromethane (3 mL) was addedtrifluoroacetic acid (1 mL). The mixture was stirred at room temperaturefor 30 min. After completion, the solvent was removed under pressure.The residue was redissolved in dichloromethane and washed with saturatedNaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated. Themixture was purified by silica gel column withdichloromethane/methanol=50/1 to afford(3S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-(5-chloro-2,4-difluorophenyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8) (225 mg, yield: 99%) as a yellow solid. MS (ESI) m/z 670.2 [M+H]⁺.

Step 8:(3S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9)

To a mixture of(3S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-(5-chloro-2,4-difluorophenyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8) (225 mg, 0.34 mmol) and triethylamine (61 mg, 0.68 mmol) indichloromethane (5 mL) was added acrylic anhydride (43 mg, 0.34 mmol) at0° C. The mixture was stirred at 0° C. for 1 hour. After completion, themixture was purified by preparative high performance liquidchromatography (20% to 95% acetonitrile in water) to afford the product(110 mg, yield: 45%) as a light yellow solid. MS (ESI) m/z 724.2 [M+H]⁺.

The above racemate (110 mg) was separated by chiral supercritical fluidchromatography (separation condition: Column: Chiralpak AD-H 5 μm 20×250mm; Mobile Phase: CO₂:IPA=70:30 at 25 mL/min; Temp: 25° C.; Wavelength:254 nm) to afford the compound P1 (20 mg of white powder) and compoundP2 (70 mg of white powder)); Chiral HPLC Analytical: on CHIRALPAK® AD-Hwas using 5 μm 4.6×250 mm column, Mobile Phase: CO₂:IPA=70:30 at 2.5mL/min; Temp: 25° C.; Wavelength: 254 nm). P1: ¹H NMR (400 MHz, CDCl₃) δ7.84-7.82 (m, 1H), 7.26-7.23 (m, 1H), 7.07 (t, J=8.4 Hz, 1H), 6.66-6.53(m, 1H), 6.41-6.33 (m, 1H), 5.80-5.75 (m, 1H), 5.34-5.32 (m, 1H),5.05-5.04 (m, 0.5H), 4.83-4.79 (m, 1H), 4.42-4.33 (m, 5.5H), 4.06-4.02(m, 0.5H), 3.76-3.64 (m, 2H), 3.42-3.38 (m, 1H), 3.28-3.25 (m, 0.5H),3.01-2.98 (m, 1H), 2.72-2.66 (m, 1H), 2.55-2.35 (m, 5H), 1.82-1.80 (m,4H), 1.47-1.38 (m, 6H). Chiral SFC fraction 1: e.e.=100%, Rt=5.35 min.P2: δ 7.83 (s, 1H), 7.30-7.26 (m, 1H), 7.07 (t, J=8.8 Hz, 1H), 6.66-6.50(m, 1H), 6.41-6.33 (m, 1H), 5.80-5.75 (m, 1H), 5.36-5.34 (m, 1H),5.03-4.99 (m, 0.5H), 4.79-4.77 (m, 0.5H), 4.67-4.65 (m, 0.5H), 4.43-4.34(m, 5.5H), 4.09-4.06 (m, 0.5H), 3.76-3.63 (m, 2H), 3.45-3.42 (m, 1H),3.28-3.25 (m, 0.5H), 3.04-3.00 (m, 1H), 2.91-2.31 (m, 6H), 1.90-1.87 (m,4H), 1.48-1.37 (m, 6H). Chiral SFC fraction 1: e.e.=99.84%, Rt=6.34 min.

Example 1321

The title compound was prepared according to the scheme below.

Step 1: (R)-benzyl 4-(oxiran-2-ylmethyl)piperazine-1-carboxylate (2)

To a solution of (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (25.0 g,96.5 mmol) in acetonitrile (150 mL) was added benzylpiperazine-1-carboxylate (1) (19.3 g, 75.8 mmol) and potassium carbonate(24.0 g, 176 mmol) at 0° C. The mixture was stirred under nitrogenatmosphere at room temperature for 22 hours. After completion, themixture was concentrated and the residue was purified by silica gelcolumn with dichloromethane/methanol=50/1 to afford (R)-benzyl4-(oxiran-2-ylmethyl)piperazine-1-carboxylate (2) (24.5 g, crude) as alight yellow oil. MS (ESI) m/z 277.4 [M+H]⁺.

Step 2: (R)-benzyl4-(3-hydroxy-2-mercaptopropyl)piperazine-1-carboxylate (3)

To a mixture of (R)-benzyl 4-(oxiran-2-ylmethyl)piperazine-1-carboxylate(2) (24.5 g, 88.7 mmol) in tetrahydrofuran (300 mL) were added1,1,1,3,3,3-hexamethyldisilathiane (17.4 g, 97.5 mmol) andtetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 26.7 mL, 26.7mmol) at 0° C. The mixture was stirred at room temperature for 2 hours.After completion, the mixture was poured into water (300 mL), extractedwith ethyl acetate (3×200 mL). The organic phase was washed with brine(300 mL) and dried over anhydrous sodium sulfate. After filtration andconcentration, the residue was purified by silica gel column withdichloromethane/methanol=50/1 to afford (R)-benzyl4-(3-hydroxy-2-mercaptopropyl)piperazine-1-carboxylate (3) (20.8 g,yield: 76%) as a colorless oil. MS (ESI) m/z 311.5 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.36-7.31 (m, 5H), 5.13 (s, 2H), 3.80-3.78 (m, 1H),3.54-3.50 (m, 4H), 3.39 (s, 1H), 2.66-2.57 (m, 4H), 2.46-2.40 (m, 4H),1.57-1.52 (m, 1H).

Step 3: (R)-benzyl4-(3-((7-chloro-4-hydroxy-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-8-yl)thio)-2-hydroxypropyl)piperazine-1-carboxylate(4)

To a solution of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (5.00 g,12.8 mmol) in dioxane (128 mL) were added potassium carbonate (5.29 g,38.4 mmol), (R)-benzyl4-(2-hydroxy-3-mercaptopropyl)piperazine-1-carboxylate (3) (3.97 g, 12.8mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (1.47 g, 2.56mmol) and tris(dibenzylideneacetone) dipalladium (1.20 g, 1.28 mmol).The mixture was stirred at 55° C. under nitrogen atmosphere for 8 hours.After completion, the mixture was diluted with tetrahydrofuran (300 mL)and filtered. The filtrate was concentrated and the residue was purifiedby silica gel column chromatography (dichloromethane/methanol=100/1 to20/1) to afford (R)-benzyl4-(3-((7-chloro-4-hydroxy-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-8-yl)thio)-2-hydroxypropyl)piperazine-1-carboxylate(4) (5.70 g, yield: 78%) as a yellow solid. MS (ESI) m/z 573.5 [M+H]⁺.

Step 4: (S)-benzyl4-((10-chloro-7-hydroxy-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperazine-1-carboxylate(5)

To a mixture of (R)-benzyl4-(3-((7-chloro-4-hydroxy-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-8-yl)thio)-2-hydroxypropyl)piperazine-1-carboxylate(4) (4.66 g, 8.1 mmol) and triphenylphosphine (4.26 g, 16.2 mmol) intetrahydrofuran (81 mL) was added diethyl azodicarboxylate (2.81 g, 16.2mmol) at 0° C. The mixture was stirred at 0° C. for 45 min. Aftercompletion, the mixture was poured into ice-water (300 mL) and extractedwith ethyl acetate (3×200 mL). After concentration, the residue waspurified by flash chromatography column (C18, acetonitrile/water=30% to95%) to afford (S)-benzyl4-((10-chloro-7-hydroxy-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperazine-1-carboxylate(5) (3.14 g, yield: 70%) as a white solid. MS (ESI) m/z 555.5 [M+H]⁺.

Step 5: (S)-benzyl4-((7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-10-chloro-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperazine-1-carboxylate(6)

To a mixture of (S)-benzyl4-((10-chloro-7-hydroxy-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperazine-1-carboxylate(5) (1.77 g, 3.19 mmol) and potassium carbonate (2.20 g, 15.9 mmol) inacetonitrile (106 mL) was added 4-methylbenzenesulfonic anhydride (2.08g, 6.38 mmol) at 25° C. The mixture was stirred at 25° C. for 3 hours.After completion, tert-butyl piperazine-1-carboxylate (1.18 g, 6.38mmol) was added into the reaction solution. The reaction mixture wasstirred at 25° C. for 1 hour. The mixture was poured into ice-water (300mL) and extracted with ethyl acetate (3×200 mL). Concentrated and theresidue was purified by flash chromatography column (C18,acetonitrile/water=20% to 95%) to afford (S)-benzyl4-((7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-10-chloro-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperazine-1-carboxylate(6) (1.43 g, yield: 63%) as a pale-white solid. MS (ESI) m/z 723.1[M+H]⁺.

Step 6: (S)-benzyl4-((7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-10-(4-fluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperazine-1-carboxylate(7)

To a solution of ((S)-benzyl4-((7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-10-chloro-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperazine-1-carboxylate(6) (1 g, 1.3 mmol) in 1,4-dioxane (15 mL) and water (3 mL) were addedtripotassium phosphate (1.1 g, 5.2 mmol), (4-fluorophenyl)boronic acid(546 mg, 3.9 mmol), and chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(202 mg, 0.26 mmol). The mixture was stirred at 85° C. under nitrogenatmosphere for 4 hours. After completion, the mixture was diluted withtetrahydrofuran (300 mL) and the insoluble was filtered out. Thefiltrate was concentrated and the residue was purified by silica gelcolumn chromatography (dichloromethane/methanol=100/1 to 30/1) to afford(S)-benzyl4-((7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-10-(4-fluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperazine-1-carboxylate(7) (1.00 g, crude) as a yellow solid. MS (ESI) m/z 783.3 [M+H]⁺.

Step 7: (S)-tert-butyl4-(10-(4-fluorophenyl)-5-oxo-3-(piperazin-1-ylmethyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)piperazine-1-carboxylate(8)

To a mixture of (S)-benzyl4-((7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-10-(4-fluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-3-yl)methyl)piperazine-1-carboxylate(7) (1.00 g, 1.20 mmol) in ethanol (15 ml) was added Pd/C (0.300 g, 30%w/w) at 25° C. The reaction solution was stirred at room temperatureunder hydrogen atmosphere for 1 hour. The mixture was filtered andconcentrated. The residue was purified by silica gel columnchromatography (dichloromethane/methanol=15/1) to afford (S)-tert-butyl4-(10-(4-fluorophenyl)-5-oxo-3-(piperazin-1-ylmethyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)piperazine-1-carboxylate(8) (600 mg, yield: 77%) as a yellow solid. MS (ESI) m/z 649.7 [M+H]⁺.

Step 8: (S)-tert-butyl4-(3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(4-fluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)piperazine-1-carboxylate(9)

To a mixture of (S)-tert-butyl4-(10-(4-fluorophenyl)-5-oxo-3-(piperazin-1-ylmethyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)piperazine-1-carboxylate(8) (600 mg, 0.93 mmol) and sodium cyanoborohydride (805 mg, 4.63 mmol)in tetrahydrofuran (5 mL) and methanol (5 mL) was added(1-ethoxycyclopropoxy)trimethylsilane (991 mg, 5.70 mmol) at 25° C.under nitrogen atmosphere. The reaction solution was heated to 85° C.for 12 hours. After completion, the mixture was filtered andconcentrated. The residue was purified by silica gel columnchromatography (dichloromethane/methanol=30/1) to afford ((S)-tert-butyl4-(3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(4-fluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)piperazine-1-carboxylate(9) (300 mg, yield: 46%) as a yellow solid. MS (ESI) m/z 689.9 [M+H]⁺.

Step 9:(S)-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(4-fluorophenyl)-7-(piperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(10)

To a cooled mixture of ((S)-tert-butyl4-(3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(4-fluorophenyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)piperazine-1-carboxylate(9) (300 mg, 0.43 mmol) in dichloromethane (5 mL) was addedtrifluoroacetic acid (1 mL) at 0° C. The reaction solution was stirredat room temperature for 1 hour. The mixture was concentrated. Theresidue was redissolved in dichloromethane and washed with saturatedNaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel column chromatography(dichloromethane/methanol=15/1) to afford(S)-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(4-fluorophenyl)-7-(piperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(10) (200 mg, yield: 79%) as a yellow solid. MS (ESI) m/z 589.8 [M+H]⁺.

Step 10:((S)-7-(4-acryloylpiperazin-1-yl)-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(4-fluorophenyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(11)

To a mixture of(S)-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(4-fluorophenyl)-7-(piperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(10) (180 mg, 0.30 mmol) and triethyl amine (56 mg, 0.56 mmol) indichloromethane (5 mL) was added acrylic anhydride (70 mg, 0.56 mmol) at0° C. The mixture was stirred at 0° C. for 1 hour. After completion, themixture was poured into ice-water (50 mL) and extracted with ethylacetate (3×20 mL). Concentrated and the residue was purified bypreparative high performance liquid chromatography (20% to 95%acetonitrile in water) to afford(S)-7-(4-acryloylpiperazin-1-yl)-3-((4-cyclopropylpiperazin-1-yl)methyl)-10-(4-fluorophenyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(11) (100 mg, yield:52%) as a white solid. MS (ESI) m/z 643.8 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.21-7.17 (m, 4H), 6.62-6.54 (m,1H), 6.41-6.31 (m, 1H), 5.82-5.76 (m, 1H), 5.35-5.29 (m, 1H), 3.97-3.73(m, 9H), 3.47-3.35 (m, 1H), 2.98-2.93 (m, 1H), 2.86-2.46 (m, 10H),0.59-0.37 (m, 4H).

Example 1357

The title compound was prepared according to the scheme below.

Step 1: (3-(mercaptomethyl)oxetan-3-yl)methanol (2)

To a solution of (3-(bromomethyl)oxetan-3-yl)methanol (1) (200 g, 1.105mmol) in ethanol (1.8 L) was added sodium hydrosulfide (176.8 g, 2.210mmol, 70% purity) at 0° C. The mixture was stirred at room temperatureunder nitrogen atmosphere for 2 hours. After completion, the mixture wasfiltered and the filtrate was concentrated to afford the crude productwhich was purified by silica gel column withdichloromethane/methanol=100/1 to afford (3-(mercaptomethyl)oxetan-3-yl)methanol (2) (64.2 g, yield: 43%) as a pale yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 4.49-4.41 (m, 4H), 3.95 (s, 2H), 2.96 (d, J=8.4 Hz, 2H), 2.06(brs, 1H), 1.36 (t, J=8.4 Hz, 1H).

Step 2:7-chloro-8-(((3-(hydroxymethyl)oxetan-3-yl)methyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(3)

To a solution of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (71.40g, 182.85 mmol) in dioxane (2200 mL) were added potassium carbonate(75.82 g, 548.56 mmol), (3-(mercaptomethyl)oxetan-3-yl)methanol (2)(49.08 g, 365.70 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene(15.87 g, 27.43 mmol) and tris(dibenzylideneacetone) dipalladium (16.75g, 18.29 mmol). The mixture was stirred at 65° C. under nitrogenatmosphere for 16 hours. After completion, the mixture was filtered andthe solid was washed with dichloromethane (1 L). (CAUTION! The organicphase contained only little product.) Then the solid was washed withtetrahydrofuran until the product was little by TLC. The tetrahydrofuranphase was concentrated and the residue was heated withtetrahydrofuran/petroleum ether (200 mL/50 mL) to afford the crudeproduct 7-chloro-8-(((3-(hydroxymethyl)oxetan-3-yl)methyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (3) (72.7g, crude) as a pale yellow solid. MS (ESI) m/z 397.0 [M+H]⁺.

Step 3:11-chloro-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetane]-6,8(4H,7H)-dione(4)

To a mixture of7-chloro-8-(((3-(hydroxymethyl)oxetan-3-yl)methyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(3) (72.7 g, 183.23 mmol) and tributylphosphine (96.12 g, 366.46 mmol)in tetrahydrofuran (7000 mL) was added diisopropylazodicarboxylate(74.10 g, 366.46 mmol) at 0° C. under nitrogen atmosphere. The mixturewas stirred at room temperature for 18 hours. After completion, themixture was poured into ice-water (7000 mL) and extracted with ethylacetate (3×7000 mL). The organic phase was concentrated and the residuewas purified by silica column (with 0.2%-1% methanol in dichloromethane)to afford the crude product11-chloro-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetane]-6,8(4H,7H)-dione (4) (34.10 g, yield:49%) as apale yellow solid. MS (ESI) m/z 376.9 [M−H]⁻.

Step 4: tert-butyl4-(11-chloro-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-8-yl)piperazine-1-carboxylate(5)

To a mixture of11-chloro-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetane]-6,8(4H,7H)-dione(4) (700 mg, 1.85 mmol) and potassium carbonate (2.55 g, 18.48 mmol) inacetonitrile (40 mL) and dichloromethane (10 mL) was added2,4,6-triisopropylbenzenesulfonyl chloride (839 mg, 2.77 mmol) at 25° C.The mixture was stirred at 25° C. for 6 hours. tert-butylpiperazine-1-carboxylate (516 mg, 2.77 mmol) was added into the reactionsolution. The reaction mixture was stirred at 25° C. for 1 hour. Themixture was poured into ice-water (50 mL) and extracted with ethylacetate (3×50 mL). The organic phase was concentrated and the residuewas purified by flash silica column (with 0.2%-1% methanol indichloromethane) to afford tert-butyl4-(11-chloro-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-8-yl)piperazine-1-carboxylate(5) (600 mg, yield: 59%) as a pale-yellow solid. MS (ESI) m/z 547.99[M+H]+.

Step 5: tert-butyl4-(11-(3-chloro-4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-8-yl)piperazine-1-carboxylate(6)

To a solution of tert-butyl4-(11-chloro-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-8-yl)piperazine-1-carboxylate(5) (150 mg, 0.27 mmol) in 1,4-dioxane (20 mL) and water (5 mL) wereadded tripotassium phosphate trihydrate (219 mg, 0.82 mmol),(3-chloro-4-fluorophenyl)boronic acid (190 mg, 1.10 mmol), andchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(21 mg, 0.03 mmol). The mixture was stirred at 85° C. under nitrogenatmosphere for 3 hours. After completion, the mixture was concentratedand the residue was purified by silica gel column chromatography (with1%-3% methanol in dichloromethane) to afford tert-butyl4-(11-(3-chloro-4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-8-yl)piperazine-1-carboxylate(6) (148 mg, yield: 84%) as a yellow solid. MS (ESI) m/z 642.1 [M+H]⁺.

Step 6:11-(3-chloro-4-fluorophenyl)-8-(piperazin-1-yl)-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-6(4H)-one(7)

To a cooled mixture of tert-butyl4-(11-(3-chloro-4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-8-yl)piperazine-1-carboxylate(6) (148 mg, 0.27 mmol) in dichloromethane (5 mL) was addedtrifluoroacetic acid (1 mL) at 0° C. The reaction solution was stirredat room temperature for 1 hour. The mixture was concentrated. Theresidue was redissolved in dichloromethane and washed with saturatedNaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated. Themixture was concentrated and the residue was purified by silica gelcolumn chromatography (with 7% methanol in dichloromethane) to afford11-(3-chloro-4-fluorophenyl)-8-(piperazin-1-yl)-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-6(4H)-one(7) (97 mg, yield: 78%) as a yellow solid. MS (ESI) m/z 542.1 [M+H]⁺.

Step 7:8-(4-acryloylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-6(4H)-one(8)

To a mixture of11-(3-chloro-4-fluorophenyl)-8-(piperazin-1-yl)-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-6(4H)-one(7) (81 mg, 0.15 mmol) and triethyl amine (23 g, 0.22 mmol) indichloromethane (2 mL) was added acrylic anhydride (22 mg, 0.18 mmol) at0° C. The mixture was stirred at 0° C. for 1 hour. The mixture waspoured into ice-water (2 mL) and extracted with ethyl acetate (3×2 mL).The organic phase was concentrated and the residue was purified bysilica gel column chromatography (with 2% methanol in dichloromethane)to afford8-(4-acryloylpiperazin-1-yl)-11-(3-chloro-4-fluorophenyl)-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,3′-oxetan]-6(4H)-one(8) (69 mg, yield: 78%) as a pale-white solid. MS (ESI) m/z 596.1.0[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 1H), 7.30-7.23 (m, 2H),7.11-7.09 (m, 1H), 6.62-6.55 (m, 1H), 6.39-6.35 (m, 1H), 5.82-5.78 (m,1H), 5.14-4.64 (m, 3.5H), 4.36-4.33 (m, 2H), 4.00-3.73 (m, 8.5H),3.42-3.39 (m, 2H).

Example 1358:(S)-7-(4-acryloylpiperazin-1-yl)-10-(4-fluorophenyl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

The title compound was prepared according to the scheme below.

Step 1: (S)-2-((methoxymethoxy)methyl)oxirane (2)

To a mixture of (R)-oxiran-2-ylmethanol (1) (15 g, 202.7 mmol) andN,N-diisopropylethylamine (52.3 g, 405.4 mmol) in dichloromethane (200mL) was added bromo(methoxy)methane (32.7 g, 263.5 mmol). The mixturewas stirred at 0° C. to room temperature for 5 hours. After completion,the mixture was poured into dichloromethane (300 mL), washed with water(3×200 mL). The organic phase was washed with brine (100 mL) and driedover anhydrous sodium sulfate. After filtration and concentration, theresidue was purified by silica gel column with petroleum ether to afford(S)-2-((methoxymethoxy)methyl)oxirane (2) (25.00 g, crude) as colorlessoil; ¹H NMR (400 MHz, CDCl₃) δ 4.66 (d, J=1.2 Hz, 2H), 3.79 (dd, J=11.6Hz, 3.2 Hz, 1H), 3.51 (dd, J=11.6 Hz, 2.0 Hz, 1H), 3.38 (s, 3H),3.20-3.16 (m, 1H), 2.83-2.80 (m, 1H), 2.64 (dd, J=5.2 Hz, 2.8 Hz, 1H).

Step 2: (R)-1-mercapto-3-(methoxymethoxy)propan-2-ol (3)

To a mixture of (S)-2-((methoxymethoxy)methyl)oxirane (2) (10 g, 84.7mmol) in tetrahydrofuran (250 mL) was added1,1,1,3,3,3-hexamethyldisilathiane (16.63 g, 93.2 mmol) andtetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 25 mL, 25 mmol)at 0° C. The mixture was stirred at room temperature for 2 hours. Aftercompletion, the mixture concentrated under reduced pressure, the residuewas purified by silica gel column with petroleum ether/ethyl acetate=4/1to afford (R)-1-mercapto-3-(methoxymethoxy)propan-2-ol (3) (2 g, yield:16%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 4.66 (s, 2H),3.85-3.82 (m, 1H), 3.69-3.60 (m, 2H), 3.39 (s, 3H), 2.88 (brs, 1H),2.71-2.65 (m, 2H), 1.51 (t, J=8.8 Hz, 1H).

Step 3:(R)-7-chloro-4-hydroxy-8-((2-hydroxy-3-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(4)

To a solution of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (1.86 g,4.77 mmol) in dioxane (40 mL) were added potassium carbonate (1.32 g,9.54 mmol), (R)-1-mercapto-3-(methoxymethoxy)propan-2-ol (3) (1.09 g,7.15 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (413 mg,0.72 mmol) and tris(dibenzylideneacetone) dipalladium (439 g, 0.48mmol). The mixture was stirred at 60° C. under nitrogen atmosphere for18 hours. After completion, the mixture was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(dichloromethane/methanol=60/1) to afford(R)-7-chloro-4-hydroxy-8-((2-hydroxy-3-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(4) (1.33 g, yield: 67%) as pale yellow solid. MS (ESI) m/z 415.0[M+H]⁺.

Step 4:(S)-10-chloro-7-hydroxy-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5)

To a mixture of(R)-7-chloro-4-hydroxy-8-((2-hydroxy-3-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(4) (1.33 g, 3.21 mmol) and triphenylphosphine (3.37 g, 12.85 mmol) intetrahydrofuran (500 ml) was added diethyl azodicarboxylate (4.71 g,12.85 mmol) at 0° C. The mixture was stirred at 0° C. for 45 min. Aftercompletion, the mixture was poured into ice-water (200 mL) and extractedwith ethyl acetate (3×200 mL). Concentrated and the residue was purifiedby C18 with 30-95% acetonitrile in water to afford(S)-10-chloro-7-hydroxy-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5) (1.1 g, yield: 87%) as a pale yellow solid. MS (ESI) m/z 397.0[M+H]⁺.

Step 5: (S)-tert-butyl4-(10-chloro-3-((methoxymethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)piperazine-1-carboxylate(6)

To a mixture of(S)-10-chloro-7-hydroxy-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5) (1.5 g, 3.78 mmol) and potassium carbonate (5.21 g, 37.8 mmol) inacetonitrile (35 mL) was added 4-methylbenzenesulfonic anhydride (3.08g, 9.45 mmol) at 0° C. The mixture was stirred at room temperature for 4hours. After completion, tert-butyl piperazine-1-carboxylate (2.82 g,15.12 mmol) was added into the reaction solution. The reaction mixturewas stirred at 0° C. for 1 hour. After completion, the mixture waspoured into ice-water (50 mL) and extracted with ethyl acetate (3×50mL). After concentration, the residue was purified by C18 column with20-95% acetonitrile in water to afford (S)-tert-butyl4-(10-chloro-3-((methoxymethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)piperazine-1-carboxylate(6) (1.7 g, yield: 81%) as a white solid. MS (ESI) m/z 565.2 [M+H]⁺.

Step 6: (S)-tert-butyl4-(10-(4-fluorophenyl)-3-((methoxymethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)piperazine-1-carboxylate(7)

To a solution of (S)-tert-butyl4-(10-chloro-3-((methoxymethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)piperazine-1-carboxylate(6) (300 mg, 0.53 mmol) in 1,4-dioxane (10 mL) and water (2 mL) wasadded tripotassium phosphate (423 mg, 1.59 mmol),(4-fluorophenyl)boronic acid (418 mg, 2.65 mmol) andchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(41 mg, 0.05 mmol). The mixture was stirred at 80° C. under nitrogenatmosphere for 2 hours. After completion, the mixture was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (dichloromethane/methanol=100/1) to afford (S)-tert-butyl4-(10-(4-fluorophenyl)-3-((methoxymethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)piperazine-1-carboxylate(7) (350 mg, crude) as a yellow solid. MS (ESI) m/z 625.3 [M+H]⁺.

Step 7:(S)-10-(4-fluorophenyl)-3-((methoxymethoxy)methyl)-7-(piperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a cooled mixture of (S)-tert-butyl4-(10-(4-fluorophenyl)-3-((methoxymethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)piperazine-1-carboxylate(7) (350 mg, 0.56 mmol) in dichloromethane (8 mL) was addedtrifluoroacetic acid (2 mL) at 0° C. The reaction solution was stirredat room temperature for 1 hour. The solvent was removed under pressure.The residue was redissolved in dichloromethane and washed with saturatedNaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel column chromatography(dichloromethane/methanol=10/1) to afford(S)-10-(4-fluorophenyl)-3-((methoxymethoxy)methyl)-7-(piperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8) (180 mg, three steps yield: 61%) as a yellow solid. MS (ESI) m/z525.2 [M+H]⁺.

Step 8:(S)-7-(4-acryloylpiperazin-1-yl)-10-(4-fluorophenyl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9)

To a mixture of(S)-10-(4-fluorophenyl)-3-((methoxymethoxy)methyl)-7-(piperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8) (180 mg, 0.34 mmol) and triethyl amine (104 mg, 1.03 mmol) indichloromethane (5 ml) was added acrylic anhydride (64 mg, 0.51 mmol) at0° C. The mixture was stirred at 0° C. for 1 hour. After completion, themixture was poured into ice-water (30 mL) and extracted withdichloromethane (3×30 mL). After concentration, the residue was purifiedby preparative High Performance Liquid Chromatography (20% to 95%acetonitrile in water) to afford(S)-7-(4-acryloylpiperazin-1-yl)-10-(4-fluorophenyl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9) (80 mg, yield: 41%) as a white solid. MS (ESI) m/z 579.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.24-7.15 (m, 4H), 6.63-6.56 (m,1H), 6.39 (d, J=16.4 Hz, 1H), 5.80 (d, J=10.4 Hz, 1H), 5.46-5.45 (m,1H), 4.67-4.62 (m, 2H), 4.02-3.95 (m, 3H), 3.81-3.79 (m, 7H), 3.35-3.33(m, 4H), 3.01-2.98 (m, 1H).

Example 1366a:(3S,10S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(4-fluoro-1-methyl-1H-indazol-7-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

The title compound was prepared according to the scheme below.

Step 1: (E)-2-(3-Bromo-2,6-difluorobenzylidene)-1-methylhydrazin-1-iumchloride

3-Bromo-2,6-difluorobenzaldehyde (5.5 g, 24.9 mmol, 1 equiv) was addedto a 250 mL round-bottom flask under a N₂ atmosphere and dissolved in1,2-dichloroethane (260 mL). Next, tert-butyl1-methylhydrazine-1-carboxylate (5.2 mL, 34.86 mmol, 1.4 equiv, den.0.985 g/mL) was added by syringe and the reaction mixture was stirred atroom temperature. After 16 hours, the solvent was removed by rotaryevaporation (full conversion determined by LC-MS). The resulting orangeliquid was cooled to 0° C. and 4N HCl in 1,4-dioxane (60 mL) was addedin portions (ca. 10 min). After 30 minutes, the ice-bath was removed,and the reaction mixture was stirred at room temperature for 1 hour. Theresulting white precipitate was collected using a Büchner funnel, washedwith Et₂O (150 mL) and dried under high vacuum to afford(E)-2-(3-bromo-2,6-difluorobenzylidene)-1-methylhydrazin-1-ium chlorideas an off-white solid (6.9 g, 97%): ¹H NMR (400 MHz, DMSO-d₆) δ8.89-8.27 (br s, 1H), 7.60-7.51 (m, 1H), 7.35-7.24 (m, 1H), 7.10 (t,J=10.0 Hz, 1H), 2.84 (s, 2H), 2.59 (s, 1H); LRMS-ESI (m/z) [M+H]⁺calculated for C₈H₈BrF₂N₂ 248.98, found 249.0.

Step 2: 7-Bromo-4-fluoro-1-methyl-1H-indazole

Sodium hydride (60 wt % in mineral oil, 2.2 g, 54.6 mmol, 5.2 equiv) wasadded to a 100 mL round-bottom flask under a N₂ atmosphere and purgedwith N₂ for 30 min prior to the addition of DMF (40 mL). Next,(E)-2-(3-bromo-2,6-difluorobenzylidene)-1-methylhydrazin-1-ium chloride(3.0 g, 10.5 mmol, 1 equiv) was added to the flask at room temperaturein two portions and the resulting mixture was placed in a 60° C. oilbath and stirred. After 1 hour, additional sodium hydride (60 wt % inmineral oil, 420 mg, 10.5 mmol, 1 equiv) was added at 60° C. After 3 h,the flask was removed from the oil bath, cooled 0° C., and saturatedaqueous NH₄Cl (ca. 2 mL) was slowly added to the mixture. The resultingsolution was transferred to a separatory funnel using EtOAc (300 mL).The organic layer was washed with saturated aqueous NH₄Cl (50 mL), H₂O(3×50 mL), and the solvent was removed by rotary evaporation. The crudematerial was purified by flash column chromatography using an IsoleraOne Biotage instrument (0-5% EtOAc/hexanes, 50 g column, 0% (5 CV), 0-5%(10 CV), 5% (5 CV)), to provide the title compound (1 g, 41%) as anorange solid: TLC (5% EtOAc/hexanes) R_(f)=0.28; ¹H NMR (400 MHz, CDCl₃)δ 8.03 (s, 1H), 7.44 (dd, J=8.2, 4.5 Hz, 1H), 6.65 (t, J=8.6 Hz, 1H),4.42 (s, 3H); LRMS-ESI (m/z) [M+H]⁺ calculated for C₈H₇BrFN₂ 228.98,found 229.1.

Step 3:4-Fluoro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

7-Bromo-4-fluoro-1-methyl-1H-indazole (200 mg, 0.87 mmol, 1 equiv) wasdissolved in 1,4-dioxane (12 mL, 0.07 M) in a 50 mL bomb-flask. Theresulting mixture was purged with N₂ for 30 min prior to the addition ofPd(dppf)Cl₂ (64 mg, 0.087 mmol, 10 mol %), KOAc (171 mg, 1.74 mmol, 2equiv), and B₂(pin)₂ (265 mg, 1.044 mmol, 1.2 equiv), and then bubbledwith N₂ for an additional 5 min. The flask placed on a heated block at90° C. An additional 200 mg batch was set up using the same procedure.After 2 h, both batches were combined and filtered through Celite 545using THF (50 mL) and the solvent was removed by rotary evaporation. Thecrude material was purified by flash column chromatography using anIsolera One Biotage instrument (0-5% EtOAc/hexanes, 25 g column, 0% (5CV), 0-5% (10 CV), 5% (5 CV)), to provide the title compound (155 mg,49%) as an orange solid: TLC (5% EtOAc/hexanes) R_(f)=0.32; ¹H NMR (400MHz, CDCl₃) δ 8.08 (s, 1H), 7.87 (dd, J=7.8, 5.8 Hz, 1H), 6.77 (dd,J=9.9, 8.1 Hz, 1H), 4.33 (s, 3H), 1.40 (s, 12H); LRMS-ESI (m/z) [M+H]⁺calculated for C₁₄H₁₉BFN₂O₂ 277.15, found 277.2.

Step 4: tert-butyl(2S,6R)-4-((3S,10S)-10-(4-fluoro-1-methyl-1H-indazol-7-yl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(2)

Compound 1 (25 mg, 0.044 mmol, 1 equiv) was dissolved in 1,4-dioxane andH₂O (0.45 mL, 0.05 mL, respectively, 0.09 M). The resulting mixture waspurged with N₂ for 30 min prior to the addition of RuPhos Pd G2 (5.1 mg,0.0066 mmol, 15 mol %), K₃PO₄ (28 mg, 0.132 mmol, 3 equiv), and4-fluoro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(36.4 mg, 0.132 mmol, 3 equiv). The microwave vial was fitted with acrimp-top cap, bubbled with N₂ for an additional 5 min, and placed on aheated block at 85° C. The resulting reaction mixture was homogenous.After 5 hours, the vial was removed from the heating block, allowed tocool, and the solvent was removed by rotary evaporation. The crudematerial was purified by preparative thin-layer chromatography (SilicaGel 60 F₂₅₄, 0.5 mm, 20×20 cm, 2 plates) using 3% MeOH/CH₂Cl₂ to provide15 mg of compound 2 as a yellow oil in decent purity. The material wasused in the subsequent step: TLC (3% MeOH/CH₂Cl₂) R_(f)=0.27; ¹H NMR(400 MHz, MeOH-d₄) δ 8.21 (s, 1H), 8.16 (s, 1H), 7.18 (dd, J=8.0, 4.7Hz, 1H), 6.97 (dd, J=9.7, 8.0 Hz, 1H), 5.39-5.32 (m, 1H), 4.45-4.14 (m,4H), 3.73-3.60 (m, 2H), 3.56 (s, 3H), 3.49-3.33 (m, 3H), 3.36 (s, 3H),3.15 (dd, J=13.6, 3.0 Hz, 1H), 1.53 (d, J=7.0 Hz, 3H), 1.51 (s, 9H),1.35 (d, J=6.8 Hz, 3H); LRMS-ESI (m/z) [M+H]⁺ calculated forC₃₂H₃₇F₄N₆O₄S 677.25, found 677.3.

Step 5:(3S,10S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(4-fluoro-1-methyl-1H-indazol-7-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(3)

The reactions of deBoc and acrylation were carried out by using the sameprocedures described in other examples. 2.5 mg (yield: 19%) of titlecompound 3 was obtained as white solid. ¹H NMR (400 MHz, MeOH-d₄) δ 8.22(s, 1H), 8.16 (s, 1H), 7.18 (dd, J=8.0, 4.8 Hz, 1H), 6.98 (dd, J=9.7,7.9 Hz, 1H), 6.85 (dd, J=16.7, 10.6 Hz, 1H), 6.30 (dd, J=16.6, 2.0 Hz,1H), 5.81 (dd, J=10.6, 2.0 Hz, 1H), 5.41-5.31 (m, 1H), 4.84-4.55 (m,2H), 4.39 (d, J=13.6 Hz, 1H), 4.30 (d, J=13.6 Hz, 1H), 3.74-3.60 (m,3H), 3.56 (s, 3H), 3.55-3.37 (m, 3H), 3.36 (s, 3H), 3.35-3.33 (m, 1H),3.15 (dd, J=13.7, 3.0 Hz, 1H), 1.60 (d, J=6.9 Hz, 3H), 1.42 (d, J=7.0Hz, 3H); LRMS-ESI (m/z) [M+H]⁺ calculated for C₃₀H₃₁F₄N₆O₃S 631.21,found 631.3.

Example 1375 and 1376:(3S,10R)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-3-((dimethylamino)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(P1) and(3S,10S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-3-((dimethylamino)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(P2)

The title compounds were prepared according the scheme below.

Step 1: (S)—N,N-dimethyl-1-(oxiran-2-yl)methanamine (2)

The solution of (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (35 g, 135mmol) in acetonitrile (150 mL) was added dimethylamine hydrochloride(10.0 g, 122.7 mmol) and potassium carbonate (50.8 g, 368.1 mmol) at 0°C. under nitrogen atmosphere. The mixture was stirred under nitrogenatmosphere at room temperature for 16 hours. After completion, themixture was concentrated and the residue was purified by silica gelcolumn with dichloromethane/methanol=30/1 to afford the product (2) (3.5g, yield: 28%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 3.10-3.06(m, 1H), 2.78 (t, J=4.8 Hz, 1H), 2.68-2.63 (m, 1H), 2.50-2.48 (m, 1H),2.33 (s, 6H), 2.27-2.22 (m, 1H).

Step 2: (R)-1-(dimethylamino)-3-mercaptopropan-2-ol (3)

To a mixture of (S)—N,N-dimethyl-1-(oxiran-2-yl)methanamine (2) (3 g,29.7 mmol) in tetrahydrofuran (30 mL) were added1,1,1,3,3,3-hexamethyldisilathiane (5.3 g, 29.7 mmol) andtetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 9 mL, 8.9 mmol)at 0° C. The mixture was stirred at room temperature for 2 hours. Aftercompletion, the mixture was concentrated under reduced pressure toafford crude (R)-1-(dimethylamino)-3-mercaptopropan-2-ol (3) (4.5 g,crude) as yellow solid.

Step 3:(R)-7-chloro-8-((3-(dimethylamino)-2-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(4)

To a solution of7-chloro-4-hydroxy-8-iodo-6-(trifluoromethyl)quinazolin-2(1H)-one (3.86g, 9.90 mmol) in dioxane (120 mL) were added potassium carbonate (4.1 g,29.7 mmol), crude (R)-1-(dimethylamino)-3-mercaptopropan-2-ol (4.5 g),4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (858 mg, 1.48 mmol) andtris(dibenzylideneacetone) dipalladium (905 mg, 0.99 mmol). The mixturewas stirred at 60° C. under nitrogen atmosphere for 18 hours. Aftercompletion, the mixture was diluted with tetrahydrofuran (200 mL) andthe insoluble was filtered out. The filtrate was concentrated and theresidue was purified by silica gel column chromatography(dichloromethane/ammonia methanol=20/1) to afford(R)-7-chloro-8-((3-(dimethylamino)-2-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(4) (1.8 g, yield: 46%) as a yellow solid. MS (ESI) m/z 398.1 [M+H]⁺.

Step 4:(S)-10-chloro-3-((dimethylamino)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(5)

To a mixture of(R)-7-chloro-8-((3-(dimethylamino)-2-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(1.7 g, 4.28 mmol) and triphenylphosphine (3.36 g, 12.84 mmol) intetrahydrofuran (420 mL) was added diethyl azodicarboxylate (2.23 g,12.84 mmol) at 0° C. The mixture was stirred at 0° C. for 45 min. Aftercompletion, the mixture was poured into ice-water (200 mL) and extractedwith ethyl acetate (3×200 mL). Concentrated and the residue was purifiedby flash chromatography column (C18, acetonitrile/water=30% to 95%) toafford(S)-10-chloro-3-((dimethylamino)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(5) (1.08 g, yield: 67%) as a pale yellow solid. MS (ESI) m/z 380.2[M+H]⁺.

Step 5: (2S,6R)-tert-butyl4-((S)-10-chloro-3-((dimethylamino)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6)

To a mixture of(S)-10-chloro-3-((dimethylamino)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(5) (600 mg, 1.58 mmol) and potassium carbonate (2.18 g, 15.8 mmol) inacetonitrile (15 mL) was added 4-methylbenzenesulfonic anhydride (1.03g, 3.16 mmol) at 25° C. The mixture was stirred at 25° C. for 3 hours.(2R,6S)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (1 g, 4.75 mmol)was added into the reaction solution. The reaction mixture was stirredat 25° C. for 1 hour. After completion, the mixture was poured intoice-water (50 mL) and extracted with ethyl acetate (3×50 mL). Themixture was concentrated and the residue was purified by flashchromatography column (C18, acetonitrile/water=20% to 95%) to afford(2S,6R)-tert-butyl4-((S)-10-chloro-3-((dimethylamino)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6) (600 mg, yield: 66%) as a pale yellow solid. MS (ESI) m/z 576.3[M+H]⁺.

Step 6: (2S,6R)-tert-butyl4-((3S)-10-(5-chloro-2,4-difluorophenyl)-3-((dimethylamino)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(7)

To a solution of (2S,6R)-tert-butyl4-((S)-10-chloro-3-((dimethylamino)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6) (400 mg, 0.7 mmol) in 1,4-dioxane (7 mL) and water (1 mL) were addedtripotassium phosphate (559 mg, 2.1 mmol),2-(5-chloro-2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(955 mg, 3.48 mmol), and chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(54 mg, 0.07 mmol). The mixture was stirred at 85° C. under nitrogenatmosphere for 4 hours. After completion, the mixture was concentratedand the residue was purified by silica gel column chromatography(dichloromethane/methanol=60/1) to afford (2S,6R)-tert-butyl4-((3S)-10-(5-chloro-2,4-difluorophenyl)-3-((dimethylamino)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(7) (400 mg, yield: 83%) as a yellow solid. MS (ESI) m/z 688.1 [M+H]⁺.

Step 7:(3S)-10-(5-chloro-2,4-difluorophenyl)-3-((dimethylamino)methyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a cooled mixture of (2S,6R)-tert-butyl4-((3S)-10-(5-chloro-2,4-difluorophenyl)-3-((dimethylamino)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(7) (400 mg, 0.58 mmol) in dichloromethane (4 mL) was addedtrifluoroacetic acid (2 mL) at 0° C. The reaction solution was stirredat room temperature for 1 hour. After completion, the mixture wasconcentrated. The residue was redissolved in dichloromethane and washedwith saturated NaHCO₃. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel columnchromatography (dichloromethane/ammonia methanol=30/1) to afford(3S)-10-(5-chloro-2,4-difluorophenyl)-3-((dimethylamino)methyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8) (309 mg, yield: 91%) as a yellow solid. MS (ESI) m/z 588.1 [M+H]⁺.

Step 8:(3S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-3-((dimethylamino)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9)

To a mixture of(3S)-10-(5-chloro-2,4-difluorophenyl)-3-((dimethylamino)methyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(309 mg, 0.526 mmol) and triethyl amine (8) (159 mg, 1.578 mmol) indichloromethane (5 mL) was added acrylic anhydride (66 mg, 0.526 mmol)at 0° C. The mixture was stirred at 0° C. for 1 hour. After completion,the mixture was poured into ice-water (50 mL) and extracted withdichloromethane (3×30 mL). The mixture was concentrated and the residuewas purified by preparative high performance liquid chromatography (20%to 95% acetonitrile in water) to afford(3S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-3-((dimethylamino)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9) (152 mg, yield: 45%) as a white solid. MS (ESI) m/z 642.1 [M+H]⁺.

The above racemate (152 mg) was dissolved in EtOH (5 mL) and separatedby chiral supercritical fluid chromatography (separation condition:Column: Chiralpak IH 5 μm 20×250 mm; Mobile Phase: Hex:EtOH=80:20 at 25mL/min; Temp: 25° C.; Wavelength: 254 nm) to afford Compound P1 (70 mg,47% yield, 100% ee) and Compound P2 (35 mg, 23% yield, 99.3% ee); ChiralHPLC Analytical: on CHIRALPAK® IH was using 5 μm 4.6×250 mm column,Mobile Phase: Hex:EtOH=80:20 at 2.5 mL/min; Temp: 25° C.; Wavelength:254 nm). P1: ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.29-7.25 (m, 1H),7.08 (t, J=8.8 Hz, 1H), 6.66-6.59 (m, 1H), 6.43-6.39 (m, 1H), 5.78 (dd,J=10.4 Hz, 2.0 Hz, 1H), 5.38-5.35 (m, 1H), 4.71-4.59 (m, 2H), 4.20-4.16(m, 2H), 3.50-3.30 (m, 3H), 3.04-3.00 (m, 1H), 2.85-2.83 (m, 1H),2.43-2.37 (m, 7H), 1.60 (d, J=7.2 Hz, 3H), 1.49 (d, J=7.2 Hz, 3H);Chiral SFC fraction 1: e.e.=100%, Rt=6.511 min. P2: ¹H NMR (400 MHz,CDCl₃) δ 8.07 (s, 1H), 7.29-7.25 (m, 1H), 7.07 (t, J=8.8 Hz, 1H),6.66-6.59 (m, 1H), 6.43-6.39 (m, 1H), 5.78 (dd, J=10.0 Hz, 2.0 Hz, 1H),5.40-5.38 (m, 1H), 4.69-4.58 (m, 2H), 4.20-4.17 (m, 2H), 3.51-3.30 (m,3H), 3.02-2.78 (m, 2H), 2.37-2.23 (m, 7H), 1.61 (d, J=7.2 Hz, 3H), 1.48(d, J=7.2 Hz, 3H); Chiral SFC fraction 1: e.e.=99.3%, Rt=11.174 min.

Example 1383:(3S)-7-(7-acryloyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-10-(4-fluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

The title compound was prepared according to the scheme below.

Step 1: tert-butyl9-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate(2)

Compound 1 (100 mg, 0.273 mmol, 1 equiv) was dissolved in MeCN (2.7 mL,0.1 M) under a N₂ atmosphere in a 25 mL round bottom flask containing 3Å molecular sieves. The resulting solution was stirred for ca. 30 min atroom temperature. Next, Et₃N (114 μL, 0.819 mmol, 3 equiv) was added bysyringe followed by Ts₂O (178 mg, 0.546 mmol, 2 equiv). The mixture wasallowed to stir at room temperature for 19 hours. LCMS showed 90%conversion. Next, tert-butyl3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (125 mg, 0.546 mmol, 2equiv) and Et₃N (76 μL, 0.546 mmol, 2 equiv) was dissolved in MeCN (2mL) under a N₂ atmosphere in a 10 mL round bottom flask containing 3 Åmolecular sieves. The resulting solution was stirred for ca. 30 min atroom temperature. This solution was then added to the reaction mixtureand stirred for an additional 1 hour. The intermediate was determined tobe fully consumed by LC-MS and the solvent was removed by rotaryevaporation. The crude material was purified by flash columnchromatography using an Isolera One Biotage instrument (0-75%EtOAc/hexanes, 10 g column, 0% (5 CV), 0-50% (10 CV), 50-75% (5 CV), 75%(10 CV)), to provide compound 2 (109 mg) as a pale-yellow solid: TLC(50% EtOAc/hexanes) R_(f)=0.05; ¹H NMR (400 MHz, CDCl₃) δ 7.61 (s, 1H),5.43 (tt, J=5.7, 2.9 Hz, 1H), 4.48 (dd, J=29.7, 13.7 Hz, 1H), 4.37-3.96(m, 6H), 3.95-3.81 (m, 1H), 3.74-3.46 (m, 4H), 3.42 (s, 3H), 3.41-3.16(m, 1H), 3.10 (dd, J=13.6, 2.9 Hz, 1H), 1.49 (s, 9H); LRMS-ESI (m/z)[M+H]⁺ calculated for C₂₄H₂₉ClF₃N₄O₅S 577.15, found 577.2.

Step 2: tert-butyl9-((S)-10-(4-fluorophenyl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate(3)

Compound 2 (50 mg, 0.087 mmol, 1 equiv) was dissolved in 1,4-dioxane andH₂O (2.6 mL, 0.6 mL, respectively, 0.03 M). The resulting mixture waspurged with N₂ for 30 min prior to the addition of RuPhos Pd G4 (7.4 mg,0.0087 mmol, 10 mol %), K₃PO₄ (55 mg, 0.261 mmol, 3 equiv), and4-fluorophenylboronic acid (61 mg, 0.435 mmol, 5 equiv). The microwavevial was fitted with a crimp-top cap, bubbled with N₂ for an additional5 min, and placed on a heated block at 80° C. The resulting reactionmixture was homogenous. LCMS showed full conversion after 1 hour. Thevial was removed from the heating block, allowed to cool, and thesolvent was removed by rotary evaporation. The crude material waspurified by flash column chromatography using an Isolera One Biotageinstrument (0-100% EtOAc/hexanes, 10 g column, 0% (5 CV), 0-75% (10 CV),75% (5 CV), 75-100% (2 CV), 100% (5 CV)), to provide title compound 3(30 mg, 55%) as a white solid: TLC (50% EtOAc/hexanes) R_(f)=0.06; ¹HNMR (400 MHz, CDCl₃) δ 7.67 (s, 1H), 7.24-7.12 (m, 2H), 5.42-5.30 (m,1H), 4.60-4.26 (m, 5H), 4.26-3.84 (m, 5H), 3.79-3.52 (m, 4H), 3.39 (s,3H), 3.48-3.20 (m, 3H), 2.97 (dd, J=13.5, 2.9 Hz, 1H), 1.48 (s, 9H);LRMS-ESI (m/z) [M+H]⁺ calculated for C₃₀H₃₃F₄N₄O₅S 637.21, found 637.3.

Step 3:(3S)-7-(7-acryloyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-10-(4-fluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(4)

The reactions of deBoc and acrylation were carried out by using sameprocedure described in other examples. 22 mg (yield: 79%) of titlecompound 4 was obtained as white solid. ¹H NMR (400 MHz, MeOH-d₄) δ 7.85(d, J=3.2 Hz, 1H), 7.35-7.19 (m, 4H), 6.84 (ddd, J=17.3, 10.7, 7.0 Hz,1H), 6.21 (d, J=16.7, 1H), 5.77 (d, J=10.7 Hz, 1H), 5.36-5.26 (m, 1H),4.89-4.76 (m, 1H), 4.57-4.36 (m, 3H), 4.25-4.16 (m, 1H), 4.13-3.89 (m,4H), 3.81-3.69 (m, 2H), 3.65-3.53 (m, 2H), 3.40 (s, 3H), 3.39-3.24 (m,4H), 3.09 (dd, J=13.7, 2.8 Hz, 1H); LRMS-ESI (m/z) [M+H]⁺ calculated forC₂₈H₂₇F₄N₄O₄S 591.17, found 591.2.

Example 1407 and 1408:(R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(methoxymethyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(P1) and(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(methoxymethyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(P2)

Step 1: 5-(methoxymethyl)-2,2-dimethyl-1,3-dioxane (2)

To a solution of (2,2-dimethyl-1,3-dioxan-5-yl)methanol (1) (14.6 g, 100mmol) in tetrahydrofuran (200 mL) was added sodium hydride (12.2 g, 300mmol) at 0° C. The mixture was stirred at room temperature for 0.5 hour.Then, iodomethane (71.1 g, 500 mmol) was added to the mixture. Themixture was stirred at room temperature for 2 hours. After completion,the mixture was poured into water (100 mL), extracted with ethyl acetate(3×200 mL). The combined organic phases were washed with brine (200 mL)and dried over anhydrous sodium sulfate. After filtration andconcentration, the residue was purified by silica gel column withpetroleum ether/ethyl acetate=3/1 to afford5-(methoxymethyl)-2,2-dimethyl-1,3-dioxane (2) (12.9 g, 80%) as a yellowoil. ¹H NMR (300 MHz, CDCl₃) δ 3.95 (dd, J=4.0 Hz, J=11.6 Hz, 2H), 3.74(dd, J=6.4 Hz, J=11.6 Hz, 2H), 3.42 (d, J=6.8 Hz, 2H), 3.33 (s, 3H),2.11-1.94 (m, 1H), 1.42 (s, 3H), 1.40 (s, 3H).

Step 2: 2-(methoxymethyl)propane-1,3-diol (3)

To a solution of 5-(methoxymethyl)-2,2-dimethyl-1,3-dioxane (2) (12.9 g,80 mmol) in methanol (160 mL) was added p-toluenesulfonic acid (1.37 g,8 mmol) at room temperature. The mixture was stirred at room temperaturefor 48 hours. After completion, The mixture was concentrated, theresidue was purified by silica gel column withdichloromethane/methanol=10/1 to afford2-(methoxymethyl)propane-1,3-diol (3) (9.58 g, 99%) as a yellow oil.

Step 3: 3-hydroxy-2-(methoxymethyl)propyl 4-methylbenzenesulfonate (4)

To a solution of 2-(methoxymethyl)propane-1,3-diol (3) (9.6 g, 80 mmol)in dichloromethane (160 mL) was added triethylamine (12.1 g, 120 mmol)and p-Toluenesulfonyl chloride (12.2 g, 64 mmol). The mixture wasstirred at room temperature for 12 hours. After completion, the mixturewas concentrated, the residue was purified by silica gel column withdichloromethane/methanol=30/1 to afford3-hydroxy-2-(methoxymethyl)propyl 4-methylbenzenesulfonate (4) (8.59 g,crude) as a yellow oil.

Step 4: 3-mercapto-2-(methoxymethyl)propan-1-ol (5)

To a solution of 3-hydroxy-2-(methoxymethyl)propyl4-methylbenzenesulfonate (4) (4.0 g, 14.6 mmol) in ethanol (70 mL) wasadded sodium hydrosulfide (3.5 g, 43.8 mmol). The mixture was stirred atroom temperature for 6 hours. After completion, the mixture wasconcentrated, the residue was purified by silica gel column withdichloromethane/methanol=20/1 to afford3-mercapto-2-(methoxymethyl)propan-1-ol (5) (1.8 g, crude) as acolorless oil.

Step 5:7-chloro-8-((3-hydroxy-2-(methoxymethyl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(7)

To a solution of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (6) (1.0g, 2.5 mmol) in dioxane (50 mL) was added3-mercapto-2-(methoxymethyl)propan-1-ol (5) (523 mg, 3.8 mmol),potassium carbonate (1.03 g, 7.5 mmol),4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (289 mg, 0.5 mmol) andtris(dibenzylideneacetone) dipalladium (229 mg, 0.25 mmol). The mixturewas stirred at 55° C. for 4 hours. After completion, the mixture wasconcentrated, the residue was purified by silica gel column withdichloromethane/methanol=50/1 to afford7-chloro-8-((3-hydroxy-2-(methoxymethyl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(7) (400 mg, crude) as a white solid. MS (ESI): m/z 399.2 [M+H]⁺.

Step 6:11-chloro-3-(methoxymethyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(2H,7H)-dione(8)

To a mixture of7-chloro-8-((3-hydroxy-2-(methoxymethyl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(7) (400 mg, 1.0 mmol) and triphenylphosphine (420 mg, 1.5 mmol) intetrahydrofuran (5 mL) was added diethyl azodicarboxylate (348 mg, 2.0mmol) at 0° C. The mixture was stirred at 0° C. for 45 min. Aftercompletion, the mixture was concentrated and the residue was purified byreverse column (C18 with 5-95% ACN in H2O) to afford11-chloro-3-(methoxymethyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(2H,7H)-dione(8) (200 mg, crude) as a yellow solid. MS (ESI): m/z 381.1 [M+H]⁺.

Step 7: (2S,6R)-tert-butyl4-(11-chloro-3-(methoxymethyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(9)

To a solution of(11-chloro-3-(methoxymethyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(2H,7H)-dione(8) (200 mg, 0.52 mmol) and K₂CO₃ (359 mg, 2.6 mmol) in ACN (20 mL) wasadded p-Toluenesulfonic anhydride (169 mg, 1.04 mmol). The mixture wasstirred at room temperature for 5 hours. Then (2S,6R)-tert-butyl2,6-dimethylpiperazine-1-carboxylate (222 mg, 1.04 mmol) was added toabove mixture. The mixture was stirred at room temperature for 2 hours.After completion, the mixture was concentrated under reduced pressure,and the residue was purified by silica gel column with DCM/EA=20%-80% toafford (2S,6R)-tert-butyl4-(11-(4-fluorophenyl)-3-(methoxymethyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(9) (290 mg, crude) as a yellow solid. MS (ESI) m/z 577.5 [M+H]⁺.

Step 8: (2S,6R)-tert-butyl4-(11-(4-fluorophenyl)-3-(methoxymethyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(10)

To a solution of (2S,6R)-tert-butyl4-(11-(4-fluorophenyl)-3-(methoxymethyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(9) (290 mg, 0.5 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was addedtripotassium phosphate (390 mg, 1.5 mmol), (4-fluorophenyl)boronic acid(189 mg, 1.2 mmol) and chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(19 mg, 0.024 mmol). The mixture was stirred at 80° C. under nitrogenatmosphere for 2 hours. After completion, the mixture was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography (dichloromethane/methanol=30/1) to afford(2S,6R)-tert-butyl4-(11-(4-fluorophenyl)-3-(methoxymethyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(10) (248 mg) as a yellow solid. MS (ESI) m/z 653.3 [M+H]⁺.

Step 9:8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(methoxymethyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(11)

To a cooled mixture of (2S,6R)-tert-butyl4-(11-(4-fluorophenyl)-3-(methoxymethyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(10) (248 mg, 0.38 mmol) in dichloromethane (5 mL) was addedtrifluoroacetic acid (1 mL) at 0° C. The reaction solution was stirredat room temperature for 1 hour. The solvent was removed under pressure.The residue was redissolved in dichloromethane and washed with saturatedNaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel column chromatography (with 7%methanol in dichloromethane) to afford8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(methoxymethyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(200 mg, yield: 97%) as a yellow solid. MS (ESI) m/z 637.3 [M+H]⁺.

To a mixture of8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(methoxymethyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(200 mg, 0.37 mmol) and triethyl amine (55 mg, 0.55 mmol) indichloromethane (3 mL) was added acrylic anhydride (70 mg, 0.55 mmol) at0° C. The mixture was stirred at 0° C. for 1 hour. After completion, themixture was poured into ice-water (1 mL) and extracted with ethylacetate (3×5 mL). The organic phase was concentrated and the residue waspurified by silica gel column chromatography (with 2% methanol indichloromethane) to afford8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(methoxymethyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(11) (82 mg, yield: 38%) as a pale-yellow solid. MS (ESI) m/z 591.2[M+H]⁺.

The above racemate (82 mg) was dissolved in EtOH (150 mL) and separatedby chiral supercritical fluid chromatography (separation condition:Column: Chiralpak AD-H 5 μm 20×250 mm; Mobile Phase: Hex:EtOH=45:55 at 1mL/min; Temp: 30° C.; Wavelength: 254 nm) to afford the title compoundsP1 (40 mg, 48% yield) and P2 (42 mg, 42% yield); Chiral HPLC Analytical:on CHIRALPAK® AD-H was using 5 μm 4.6×250 mm column, Mobile Phase:Hex:EtOH=45:55 at 1 mL/min; Temp: 30° C.; Wavelength: 254 nm). P1: ¹HNMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.23-7.15 (m, 4H), 6.63 (dd, J=2.0Hz, J=16.4 Hz, 1H), 6.41 (dd, J=1.6 Hz, J=14.4 Hz, 1H), 5.77 (dd, J=2.0Hz, J=10.4 Hz, 1H), 4.67-4.62 (m, 4H), 4.16 (d, J=13.2 Hz, 2H),3.52-3.46 (m, 1H), 3.35-3.31 (m, 6H), 3.26-3.18 (m, 1H), 3.02 (dd, J=4.4Hz, J=14.8 Hz, 1H), 2.76-2.58 (m, 1H), 1.57-1.53 (m, 6H). P2: ¹H NMR(400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.23-7.15 (m, 4H), 6.62 (dd, J=10.4 Hz,J=16.8 Hz, 1H), 6.41 (dd, J=1.6 Hz, J=16.4 Hz, 1H), 5.77 (dd, J=2.0 Hz,J=10.4 Hz, 1H), 4.73-4.52 (m, 4H), 4.16 (d, J=12.8 Hz, 2H), 3.56-3.44(m, 1H), 3.35-3.26 (m, 6H), 3.23-3.19 (m, 1H), 3.02 (dd, J=4.8 Hz,J=15.2 Hz, 1H), 2.77-2.53 (m, 1H), 1.59-1.52 (m, 6H).

Example 1409:8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3,3-bis(methoxymethyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one

The title compound was prepared according to the scheme below.

Step 1: (2-phenyl-1,3-dioxane-5,5-diyl)dimethanol (3)

Pentaerythritol (1) (54.4 g, 0.4 mol) were dissolved in water (500 mL)at 40° C. Benzaldehyde (42.4 g, 0.4 mol) and concentrated hydrochloricacid (2 mL) were added at room temperature. The reaction was stirred for16 hours. Filtered, the filter cake was added to 800 mL of water andpotassium carbonate (0.5 g). The crude product was recrystallized usingtoluene to afford the final product (2) (72.6 g, yield: 81%) as whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 7.52-7.44 (m, 2H), 7.42-7.33 (m, 3H),5.43 (s, 1H), 4.21-4.10 (m, 4H), 3.76 (d, J=12.0 Hz, 2H), 3.54 (s, 2H),2.41 (brs, 1H), 2.30 (brs, 1H).

Step 2: 5,5-bis(methoxymethyl)-2-phenyl-1,3-dioxane (4)

(2-phenyl-1,3-dioxane-5,5-diyl)dimethanol (3) (25 g, 111 mmol) wasdissolved in tetrahydrofuran (500 mL) at room temperature. Sodiumhydride (17.8 g, 444 mmol) was added at 0° C. and the reaction wasstirred for 1 hour. Iodomethane (157.9 g, 1110 mol) was added, and thereaction was stirred at room temperature overnight. The mixture waspoured into water (800 ml) and extracted with ethyl acetate (3×800 ml).The organic phase was concentrated to afford the product (4) (25 g,yield: 89%) as yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.50-7.47 (m, 2H),7.49-7.33 (m, 3H), 5.43 (s, 1H), 4.12-4.07 (m, 2H), 3.89-3.85 (m, 2H),3.71 (s, 2H), 3.40 (s, 3H), 3.30 (s, 3H), 3.21 (s, 2H).

Step 3: 2,2-bis(methoxymethyl)propane-1,3-diol (5)

To a solution of 5,5-bis(methoxymethyl)-2-phenyl-1,3-dioxane (1 g, 3.96mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2.5 mL)at 0° C. The mixture was stirred at room temperature for 16 hours. Aftercompletion, the mixture was purified by silica gel column (withdichloromethane/methanol=50/1) to afford the product (5) (400 mg, yield:60%) as pale-yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 3.65 (s, 4H), 3.45(s, 4H), 3.35 (s, 6H).

Step 4: 3-hydroxy-2,2-bis(methoxymethyl)propyl 4-methylbenzenesulfonate(6)

TsCl (5.3 g, 27.86 mmol) was added to a mixture of2,2-bis(methoxymethyl)propane-1,3-diol (4.57 g, 27.86 mmol) and triethylamine (4.22 g, 41.79 mmol) in dichloromethane (100 mL) at 0° C. Themixture was stirred at room temperature for 16 hours. After completion,the mixture was purified by silica gel column (with petroleumether/ethyl acetate=20/1) to afford the product (6) (2.2 g, yield: 25%)as pale-yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J=8.4 Hz, 2H),7.35 (d, J=8.0 Hz, 2H), 4.07 (s, 2H), 3.62 (d, J=5.2 Hz, 2H), 3.33 (s,4H), 3.25 (s, 6H), 2.52 (t, J=5.6 Hz, 1H), 2.45 (s, 3H).

Step 5: 3-mercapto-2,2-bis(methoxymethyl)propan-1-ol (7)

To a solution of 3-hydroxy-2,2-bis(methoxymethyl)propyl4-methylbenzenesulfonate (6) (8 g, 25.16 mmol) in dimethylformide (50mL) was added sodium hydrosulfide (20 g, 251.6 mmol, 70% purity) at 0°C. The mixture was stirred at 30° C. under nitrogen atmosphere for 16hours. After completion, the mixture was filtered. The filtrate wasconcentrated to afford the crude product which was purified by silicagel column (with petroleum ether/ethyl acetate=4/1) to afford3-mercapto-2,2-bis(methoxymethyl)propan-1-ol (7) (1.3 g, yield: 29%) asa pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 3.65 (s, 2H), 3.43-3.33 (m,10H), 2.65 (d, J=9.2 Hz, 2H), 1.29 (t, J=9.2 Hz, 1H).

Step 6:7-chloro-8-((3-hydroxy-2,2-bis(methoxymethyl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(9)

To a solution of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (8) (1.4g, 3.61 mmol) in dioxane (45 mL) were added potassium carbonate (1.5 g,10.83 mmol), 3-mercapto-2,2-bis(methoxymethyl)propan-1-ol (1.3 g, 7.22mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (312 mg, 0.54mmol) and tris(dibenzylideneacetone) dipalladium (329 mg, 0.36 mmol).The mixture was stirred at 60° C. under nitrogen atmosphere for 8 hours.After completion, the mixture was concentrated. The residue was purifiedby silica gel column chromatography (dichloromethane/methanol=60/1) toafford7-chloro-8-((3-hydroxy-2,2-bis(methoxymethyl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(9) (1.1 g, crude) as a yellow solid. MS (ESI) m/z 443.3 [M+H]⁺.

Step 7:11-chloro-3,3-bis(methoxymethyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione(10)

To a mixture of7-chloro-8-((3-hydroxy-2,2-bis(methoxymethyl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(9) (1.07 g, 2.42 mmol) and triphenylphosphine (1.9 g, 7.26 mmol) intetrahydrofuran (240 mL) was added diethyl azodicarboxylate (1.26 g,7.26 mmol) at 0° C. The mixture was stirred at room temperature for 45min. After completion, the mixture was poured into ice-water (100 mL)and extracted with ethyl acetate (3×100 mL). After concentration, theresidue was purified by flash chromatography column (C18,acetonitrile/water=30% to 95%) to afford11-chloro-3,3-bis(methoxymethyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione(10) (590 mg, yield: 57%) as a yellow solid. MS (ESI) m/z 425.0 [M+H]⁺.

Step 8: (2S,6R)-tert-butyl4-(11-chloro-3,3-bis(methoxymethyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(11)

To a mixture of11-chloro-3,3-bis(methoxymethyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione(10) (560 mg, 1.32 mmol) and potassium carbonate (1.82 g, 13.2 mmol) inacetonitrile (70 mL) and dichloromethane (70 mL) was added2,4,6-triisopropylbenzenesulfonyl chloride (800 mg, 2.64 mmol) at 0° C.The mixture was stirred at room temperature for 4 hours. Aftercompletion, (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (565mg, 2.64 mmol) was added into the reaction solution. The reactionmixture was stirred at 0° C. for 1 hour. After completion, the mixturewas poured into ice-water (50 mL) and extracted with ethyl acetate (3×60mL). After concentration, the residue was purified by C18 column with20-95% acetonitrile in water to afford (2S,6R)-tert-butyl4-(11-chloro-3,3-bis(methoxymethyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(11) (610 mg, yield: 75%) as a yellow solid. MS (ESI) m/z 621.4 [M+H]⁺.

Step 9: (2S,6R)-tert-butyl4-(11-(4-fluorophenyl)-3,3-bis(methoxymethyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(12)

To a solution of (2S,6R)-tert-butyl4-(11-chloro-3,3-bis(methoxymethyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(11) (150 mg, 0.24 mmol) in 1,4-dioxane (5 mL) and water (1 mL) wasadded tripotassium phosphate (192 mg, 0.72 mmol),(4-fluorophenyl)boronic acid (189 mg, 1.2 mmol) andChloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(19 mg, 0.024 mmol). The mixture was stirred at 80° C. under nitrogenatmosphere for 2 hours. After completion, the mixture was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography (dichloromethane/methanol=30/1) to afford(2S,6R)-tert-butyl4-(11-(4-fluorophenyl)-3,3-bis(methoxymethyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(12) (180 mg, crude) as a yellow solid. MS (ESI) m/z 681.5 [M+H]⁺.

Step 10:8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3,3-bis(methoxymethyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(13)

To a cooled mixture of (2S,6R)-tert-butyl4-(11-(4-fluorophenyl)-3,3-bis(methoxymethyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(12) (180 mg, 0.26 mmol) in dichloromethane (5 mL) was addedtrifluoroacetic acid (2 mL) at 0° C. The reaction solution was stirredat room temperature for 1 hour. The solvent was removed under pressure.The residue was redissolved in dichloromethane and washed with saturatedNaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel column chromatography(dichloromethane/methanol=10/1) to afford8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3,3-bis(methoxymethyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(13) (100 mg, yield: 65%) as a yellow solid. MS (ESI) m/z 581.2 [M+H]⁺.

Step 11:8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3,3-bis(methoxymethyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(14)

To a mixture of8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3,3-bis(methoxymethyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(13) (100 mg, 0.17 mmol) and triethyl amine (69 mg, 0.68 mmol) indichloromethane (5 ml) was added acrylic anhydride (43 mg, 0.34 mmol) at0° C. The mixture was stirred at 0° C. for 1 h. After completion, themixture was poured into ice-water (30 mL) and extracted withdichloromethane (3×30 mL). After concentrated, the residue was purifiedby preparative High Performance Liquid Chromatography (20% to 95%acetonitrile in water) to afford8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3,3-bis(methoxymethyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(14) (21 mg, yield: 20%) as a white solid. MS (ESI) m/z 635.3 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.04 (s, 1H), 7.22-7.14 (m, 3H), 6.66-6.59 (m,1H), 6.43 (dd, J=1.6 Hz, 16.8 Hz, 1H), 5.78 (dd, J=1.6 Hz, 10.4 Hz, 1H),4.94-4.91 (m, 1H), 4.74-4.57 (m, 2H), 4.23-4.07 (m, 3H), 3.62-3.60 (m,1H), 3.41-3.29 (m, 12H), 3.14-3.06 (m, 1H), 2.82-2.79 (m, 1H), 1.66 (d,J=5.2 Hz, 3H), 1.44 (d, J=4.4 Hz, 3H).

Example 1413:(S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-((methoxy-d3)methyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one

The title compound was prepared according to the scheme below.

Step 1: (R)-2,2-dimethyl-4-((trideuteriomethoxy)methyl)-1,3-dioxolane(2)

To a mixture of (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (1) (20 g,151.4 mmol) in THF (350 mL) was added NaH (12.1 g, 302.7 mmol). Themixture was stirred at 0° C. to room temperature for 0.5 hour, followedby addition of CD₃I (37.0 g, 237.2 mmol). The mixture was stirred atroom temperature overnight. The mixture was poured into NH₄Cl saturatedsolution (300 mL), extracted with ethyl acetate (3×200 mL). The organicphase was washed with water (100 mL) and dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducepressure to give the title compound (2) (13.0 g, crude) as yellow oil.¹H NMR (400 MHz, CDCl₃) δ 4.31-4.24 (m, 1H), 4.07-4.04 (m, 1H),3.72-3.68 (m, 1H), 3.49-3.39 (m, 2H), 1.43 (s, 3H), 1.37 (s, 3H).

Step 2: (S)-3-(trideuteriomethoxy)propane-1,2-diol (3)

The mixture of(R)-2,2-dimethyl-4-((trideuteriomethoxy)methyl)-1,3-dioxolane (2) (13.0g, crude) and HCl (12 mL) in THF (100 mL) and water (100 mL) was stirredat room temperature overnight. The solvent was evaporated and theresidue was purified by silica gel chromatography with DCM/MeOH=20/1 toafford (S)-3-(trideuteriomethoxy)propane-1,2-diol (3) (4.7 g, 49.8 mmol,50% yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 3.82-3.78 (m, 1H),3.55 (dd, J=4.4 Hz, 11.6 Hz, 1H), 3.49-3.45 (m, 2H), 3.38 (dd, J=6.8 Hz,10.4 Hz, 1H).

Step 3: (R)-2-hydroxy-3-(trideuteriomethoxy)propyl4-methylbenzenesulfonate (4)

To a mixture of (S)-3-(trideuteriomethoxy)propane-1,2-diol (3) (4.7 g,43.1 mmol) and TEA (8.9 mL, 64.6 mmol) in DCM (60 mL) was added TsCl(6.5 g, 34.4 mmol) at 0° C. The mixture was stirred at room temperatureovernight. The solvent was evaporated and the residue was purified bysilica gel chromatography (2% MeOH in DCM) to afford(R)-2-hydroxy-3-(trideuteriomethoxy)propyl 4-methylbenzenesulfonate (4)(7.7 g, crude) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=8.0Hz, 2H), 7.35 (d, 6.4 Hz, 2H), 4.08-3.95 (m, 3H), 3.43-2.45 (m, 2H).

Step 4: (R)-1-mercapto-3-(trideuteriomethoxy)propan-2-ol (5)

The mixture of (R)-2-hydroxy-3-methoxypropyl 4-methylbenzenesulfonate(4) (7.7 g, 29.5 mmol, crude) and NaSH (7.09 g, 88.7 mmol) in EtOH (100mL) was stirred at room temperature for 2 hours. The solvent wasevaporated and the residue was purified by silica gel column byPetroleum/Ethyl Acetate=1/1 to afford(R)-1-mercapto-3-(trideuteriomethoxy)propan-2-ol (5) (2.9 g, 15.2 mmol,crude) as yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 3.85-3.79 (m, 1H),3.51-3.41 (m, 2H), 2.73-2.59 (m, 2H), 1.47 (t, J=8.4 Hz, 1H).

Step 5: (R)-7-chloro-8-((2-hydroxy-3-(trideuteriomethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (6)

To the mixture of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (5.7 g,14.8 mmol) in dioxane (300 mL) was added Pd2(dba)3 (1.3 g, 1.48 mmol),XantPhos (1.7 g, 2.96 mmol),(R)-1-mercapto-3-(trideuteriomethoxy)propan-2-ol (5) (2.7 g, 22.24 mmol)and K₂CO₃ (6.13 g, 44.4 mmol). The mixture was stirred at 55° C. undernitrogen atmosphere for overnight. The mixture was concentrated and theresidue was purified by silica gel column with DCM/MeOH=20:1 to afford(R)-7-chloro-8-((2-hydroxy-3-(trideuteriomethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (6)(2.8 g, crude) as a light yellow solid. LC-MS: [M+H], m/z=388.5.

Step 6: (S)-10-chloro-3-((trifluoromethoxy)methyl)-9-(trideuteriomethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione (7)

To a mixture of (R)-7-chloro-8-((2-hydroxy-3-(trideuteriomethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (6)(2.8 g, 7.2 mmol) and triphenylphosphine (3.8 g, 14.4 mmol) in THF (50mL) was added DEAD (2.5 g, 13.5 mmol) slowly at 0° C. under nitrogenatmosphere. The mixture was stirred at room temperature for 1 h. Then,the mixture was poured into ice water (50 mL) and extracted with DCM(2×30 mL). The combined organic phase was dried over Na₂SO₄, andconcentrated. The residue was purified by silica gel column withPetroleum/Ethyl Acetate=0-50% to afford(S)-10-chloro-3-((trifluoromethoxy)methyl)-9-(trideuteriomethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione (7) (870mg, 2.24 mmol, yield: 31%) as a yellow solid. LC-MS: [M+H], m/z=370.2.

Step 7: (2S,6R)-tert-butyl4-((S)-10-chloro-5-oxo-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(8)

To a mixture of(S)-10-chloro-3-((trifluoromethoxy)methyl)-9-(trideuteriomethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione (7) (820mg, 2.16 mmol) and K₂CO₃ (2.98 g, 21.6 mmol) in ACN (20 mL) was addedP-Toluenesulfonic anhydride (1.40 g, 4.32 mmol). The mixture was stirredat room temperature for 5 hours. Followed by addition of(2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (925 mg, 4.32mmol). The mixture was stirred for 2 hours. The mixture was concentratedunder reduced pressure and purified by silica gel column withDichloromethane/Ethyl Acetate=20%-80% to afford (2S,6R)-tert-butyl4-((S)-10-chloro-5-oxo-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(8) (680 mg, yield: 49%) as yellow solid. LC-MS: m/z 566.5 [M+H]⁺.

Step 8: (2S,6R)-tert-butyl4-((S)-10-(4-fluorophenyl)-5-oxo-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(9)

To a solution of ((2S,6R)-tert-butyl4-((S)-10-chloro-5-oxo-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(8) (150 mg, 0.26 mmol) in dioxane (5 mL) and water (1 mL) was added(4-fluorophenyl)boronic acid (297 mg, 2.12 mmol), RuPhos Pd G2 (30 mg,0.03 mmol) and K3PO4 (692 m g, 2.6 mmol). The mixture was stirred at 75°C. under N2 for 2 hours. The mixture was poured into water (2 mL) andextracted with EtOAc (3×5 mL). The combined organic phases were washedwith brine (5 mL) and dried over Na2SO4. After filtration andconcentration, the residue was purified by silica gel column usingdichloromethane/methanol=50:1 to afford the (2S,6R)-tert-butyl4-((S)-10-(4-fluorophenyl)-5-oxo-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(9) (160 mg, crude) as a yellow solid. MS (ESI) m/z 626.6 [M+H]⁺.

Step 9:(S)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(10)

To a solution of (2S,6R)-tert-butyl4-((S)-10-(4-fluorophenyl)-5-oxo-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(9) (160 mg, 0.25 mmol) in DCM (3 mL) was added TFA (1 mL) at 0° C. Themixture was stirred at room temperature for 1 h. The solvent was removedunder pressure. The residue was redissolved in dichloromethane andwashed with saturated NaHCO₃. The organic layer was dried over Na₂SO₄.The organic solvent was concentrated under reduced pressure to afford(S)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(10) (150 mg, crude) as yellow solid. LC-MS: m/z 526.3 [M+H]⁺. 1H NMR(400 MHz, CDCl3) δ 7.78 (s, 1H), 7.21-7.17 (m, 4H), 5.43-5.37 (m, 1H),4.39 (d, J=12.4, 1H), 4.20 (d, J=11.6 Hz, 2H), 3.66-3.64 (m, 2H),3.33-3.29 (m, 1H), 3.21-3.13 (m, 1H), 2.96-2.92 (m, 3H), 2.72 (t, J=11.2Hz, 1H), 1.16-1.12 (m, 6H).

Step 10:(S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(11)

To a solution of(S)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(10) (100 mg, 0.19 mmol) and Et3N (28 mg, 0.28 mmol) in DCM (3 mL) wasadded acrylic anhydride (36 mg, 0.28 mmol) at 0° C. The mixture wasstirred at room temperature for 30 min. The mixture was quenched with 1mL of MeOH, concentrated under reduce pressure. The residue was purifiedby prep-HPLC to afford(S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(11) (57 mg, 52% yield) as a white powder. LC-MS: m/z 580.2 [M+H]⁺; 1HNMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.23-7.15 (m, 4H), 6.62 (dd, J=10.4Hz, J=16.4 Hz, 1H), 6.41 (dd, J=1.6 Hz, J=16.8 Hz, 1H), 5.77 (dd, J=2.0Hz, J=10.4 Hz, 1H), 5.43-5.41 (m, 1H), 4.82-4.54 (m, 2H), 4.21-4.16 (m,2H), 3.69-3.62 (m, 2H), 3.39-3.29 (m, 3H), 2.98-2.94 (m, 1H), 1.62 (d,J=7.2 Hz, 3H), 1.47 (d, J=7.2 Hz, 3H).

Example 1419:(S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-methyl-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

The title compound was prepared according to the scheme below.

Step 1: (R)-2-hydroxypropyl 4-methylbenzenesulfonate (2)

To a mixture of (R)-propane-1,2-diol (1) (10 g, 0.13 mol) and TEA (20.0mL, 0.195 mmol) in DCM (100 mL) was added TsCl (22.8 g, 0.12 mmol) at 0°C. After addition, the mixture was stirred at rt for 12 hours. Thesolvent was evaporated, and the residue was purified by silica gelchromatography (10-20% ethyl acetate in petroleum ether) to afford thetitle compound (2) (7.1 g, 0.031 mol, 31% yield) as colorless oil. MS(ESI) m/z 230.1 [M+H]⁺.

Step 2: (R)-1-mercaptopropan-2-ol (3)

To a mixture of (R)-2-hydroxypropyl 4-methylbenzenesulfonate (2) (7.1 g,31.0 mmol) in EtOH (100 mL) was added NaHS (2.6 g, 46.5 mmol). Themixture was stirred at 50° C. for 2.5 hours. The mixture wasconcentrated under reduce pressure, and the residue was purified bysilica gel chromatography (30-50% ethyl acetate in petroleum ether) toafford the title compound (3) (2.6 g, 28.3 mmol) as colorless oil.

Step 3:(R)-7-chloro-8-((2-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(4)

To the mixture of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (3.2 g,8.2 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (910 mg, 1.6mmol) and tris(dibenzylideneacetone) dipalladium (146.4 g, 1.6 mmol) indioxane (15 mL) was added (R)-1-mercaptopropan-2-ol (3) (1.5 g, 16.4mmol) and K₂CO₃ (3.4 g, 24.6 mmol). The mixture was stirred undernitrogen atmosphere at 60° C. for 15 hours. The mixture was concentratedand the residue was purified by silica gel column with(DCM/MeOH=50:1˜30:1) to afford the product (4) (1.68 g, 4.7 mmol, yield:57%) as a yellow solid. MS (ESI) m/z 355.1 [M+H]⁺.

Step 4:(S)-10-chloro-3-methyl-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(5)

To a mixture of6-chloro-7-(2,4-difluorophenyl)-8-(((R)-2-hydroxypropyl)thio)quinazoline-2,4(1H,3H)-dione(4) (1.2 g, 3.4 mmol) and triphenylphosphine (1.4 g, 5.0 mmol) in THF(30 mL) was added DEAD (870 mg, 5.0 mmol) slowly at 0° C. under nitrogenatmosphere. The mixture was stirred at room temperature for 1 hour. Theorganic phase was washed with water (50 mL), dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel column withPetroleum/Ethyl Acetate=0-50% to afford the product (5) (570 mg, 1.7mmol, yield: 50%) as a yellow solid. LC-MS: [M−H], m/z=337.2.

Step 5: (2S,6R)-tert-butyl4-((S)-10-chloro-3-methyl-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6)

To a solution of(S)-10-chloro-3-methyl-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(5) (512 mg, 1.7 mmol) and K₂CO₃ (1.17 g, 8.5 mmol) in ACN (2 mL) wasadded 2,4,6-triisopropylbenzenesulfonyl chloride (770 mg, 2.55 mmol).The mixture was stirred at rt for 5 hours, then the (2S,6R)-tert-butyl2,6-dimethylpiperazine-1-carboxylate (117 mg, 0.41 mmol) was added tothe reaction mixture. The reaction mixture was stirred at 0° C. for 1hour. After completion, the resulting mixture was concentrated underreduced pressure and the residue was purified by silica gel column withPetroleum/Ethyl Acetate=20%-80% to afford desired product (6) (423 mg,0.8 mmol) as yellow solid. LC-MS: m/z 533.2 [M+H]⁺;

Step 6:(2S,6R)-tert-butyl-((S)-10-(4-fluorophenyl)-3-methyl-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(7)

To a solution of (2S,6R)-tert-butyl4-((S)-10-chloro-3-methyl-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6) (180 mg, 0.34 mmol) in 1,4-dioxane (5 mL) and water (0.7 mL) wereadded tripotassium phosphate trihydrate (212 mg, 1 mmol),(4-fluorophenyl)boronic acid (420 g, 1.0 mmol), andchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(30 mg, 0.04 mmol). The mixture was stirred at 85° C. under nitrogenatmosphere for 3 hours. After completion, the mixture was concentrated.The residue was purified by silica gel column chromatography (with 1%-3%methanol in dichloromethane) to afford the product (7) (167 mg, crude)as a yellow solid. MS (ESI) m/z 593.2 [M+H]⁺.

Step 7:(S)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-methyl-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a solution of(2S,6R)-tert-butyl-((S)-10-(4-fluorophenyl)-3-methyl-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(7) (167 mg, crude) in dichloromethane (3 mL) was added TFA (1 mL) at20° C. The mixture was stirred at room temperature for 1 hour. Thesolvent was removed under pressure. The residue was redissolved indichloromethane and washed with saturated NaHCO₃. The organic layer wasdried over Na₂SO₄ and concentrated. The residue was purified by silicagel column chromatography (with 1%-3% methanol in dichloromethane) toafford the product (8) (105 mg, 0.21 mmol). MS (ESI) m/z 493.2 [M+H]⁺.

Step 8:(S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-methyl-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9)

To a mixture of(S)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-methyl-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8) (95 mg, 0.19 mmol) and triethyl amine (57 mg, 0.57 mmol) indichloromethane (3 mL) was added Acrylic Anhydride (47 mg, 0.38 mmol) at0° C. The mixture was stirred at room temperature for 1 hour. Themixture was concentrated, and the residue was purified by prep-HPLC toafford the product (45 mg, 40% yield) as white solid (9). LC-MS: m/z547.2 [M+H]+; ¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.23-7.16 (m, 4H),6.66-6.59 (m, 1H) 6.43-6.38 (m, 1H), 5.78-5.75 (m, 1H), 5.45-5.42 (m,1H), 4.78-4.53 (m, 2H), 4.21-4.15 (m, 2H), 3.38-3.27 (m, 2H), 3.14-3.10(m, 1H), 2.90-2.86 (m, 1H), 1.64 (d, J=5.2 Hz, 3H), 1.48-1.46 (m, 6H).

TABLE 10 Summary of Summary of % CAF at 10 μM after 1 hour for Examples1200-1243 Example Number CAF (% after 1 hour) 1200 73 1201 96 1202 971203 95 1204 95 1205 95 1206 92 1207 95 1208 95 1209 96 1210 94 1211 971212 50 1213 59 1214 49 1215 95 1216 94 1217 95 1218 66 1219 64 1220 671221 61 1222 59 1223 57 1224 96 1225 95 1226 81 1227 93 1228 96 1229 961230 94 1231 38 1232 93 1233 95 1234 94 1235 69 1236 94 1237 90 1238 951239 95 1240 91 1241 91 1242 70 1243 92

TABLE 11 Summary of % CAF at 10 μM after 1 hour for Examples 1300-1455 %CAF 10 uM MS @ Ex. # Structure ¹H NMR (M + H)⁺ 60 min Name 1300

¹H NMR (400 MHz, CDCl₃) δ: 8.07 (s, 1H), 7.21-7.15 (m, 1H), 7.06- 6.93(m, 2H), 6.66-6.59 (m, 1H), 6.43-6.38 (m, 1H), 5.78 (d, J = 12.0 Hz,1H), 5.28-5.26 (m, 1H), 4.66- 4.40 (m, 3H), 4.21-4.18 (m, 2H), 3.88-3.87(m, 1H), 3.68-3.31 (m, 5.5H), 2.99- 2.84 (m, 4.5H), 1.75-1.72 (m, 2H),1.61 (d, J = 6.8 Hz, 3H), 1.47 (t, J = 6.8 Hz, 3H). 662.3 90.8(3S,10S)-3- (((1S,4S)-2-oxa-5- azabicyclo[2.2.1] heptan-5-yl)methyl)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(2,4-difluorophenyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1301

¹H NMR (400 MHz, CDCl₃) δ: 8.07 (s, 1H), 7.26-7.14 (m, 1H), 7.04- 6.95(m, 2H), 6.66-6.59 (m, 1H), 6.43-6.38 (m, 1H), 5.77 (dd, J = 12.4 Hz,1H), 5.24-5.22 (m, 1H), 4.68- 4.61 (m, 1.5H), 4.40 (s, 1H), 4.18 (d, J =13.2 Hz, 2H), 3.89-3.87 (m, 1H), 3.62- 3.30 (m, 5.5H), 3.01-2.85 (m,5H), 1.75-1.71 (m, 2H), 1.62-1.60 (m, 3H), 1.49 (d, J = 6.8 Hz, 3H).662.3 96.4 (3S,10R)-3- (((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)methyl)- 7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(2,4- difluorophenyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1302

¹H NMR (400 MHz, CDCl₃) δ: 8.07 (s, 1H), 7.29-7.27 (m, 1H), 7.10- 7.04(m, 1H), 6.65-6.59 (m, 1H), 6.43-6.38 (m, 1H), 5.77 (dd, J = 10.4 Hz,1.6 Hz, 1H), 5.29-5.23 (m, 1H), 4.66-4.60 (m, 2H), 4.42- 4.41 (m, 1H),4.20-4.17 (m, 2H), 3.89-3.86 (m, 1H), 3.62-3.32 (m, 5.5H), 3.01- 2.85(m, 4.5H), 1.76-1.68 (m, 2H), 1.60 (d, J = 7.2 Hz, 3H), 1.48 (d, J = 6.8Hz, 3H). 696.2 78.9 (3S)-3-(((1S,4S)-2- oxa-5- azabicyclo[2.2.1]heptan-5-yl)methyl)- 7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-chloro- 2,4- difluorophenyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1303

¹H NMR (400 MHz, CDCl₃) δ: 7.97 (d, J = 18.4 Hz, 1H), 7.26-7.18 (m, 1H),7.12-6.98 (m, 2H), 6.76- 6.53 (m, 1H), 6.49-6.35 (m, 1H), 5.91-5.83 (m,1H), 5.48-5.41 (m, 1H), 5.23- 5.09 (m, 1H), 4.78-4.66 (m, 3H), 4.54-4.21(m, 4H), 3.89-3.57 (m, 7H), 3.48- 3.17 (m, 2H), 2.24-2.18 (m, 1H),1.66-1.52 (m, 6H). 662.3 77.6 (3S)-3-(((1S,4S)- 2-oxa-5-azabicyclo[2.2.1] heptan-5-yl)methyl)- 7-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1304

¹H NMR (400 MHz, CDCl₃) δ: 7.90 (s, 1H), 7.39-7.34 (m, 1H), 7.16- 7.10(m, 1H), 6.74-6.56 (m, 1H), 6.50-6.39 (m, 1H), 5.88-5.81 (m, 1H), 5.33-5.22 (m, 1H), 5.14-4.67 (m, 1.5H), 4.54-4.39 (m, 2H), 4.18-4.11 (m,0.5H), 4.02- 3.95 (m, 1H), 3.77-3.49 (m, 5H), 3.38-2.86 (m, 5H),1.86-1.71 (m, 3H), 1.55- 1.42 (m, 6H). 696.3 87 (3S)-3-(((1S,4S)-2-oxa-5- azabicyclo[2.2.1] heptan-5-yl)methyl)- 7-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4-dichlorophenyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1305

¹H NMR (400 MHz, CDCl₃) δ 7.88 (s, 1H), 7.29- 7.21 (m, 1H), 7.09-7.01(m, 2H), 6.71-6.62 (m, 1H), 6.47-6.41 (m, 1H), 5.86 (d, J = 14.4 Hz,1H), 5.30-5.24 (m, 1H), 4.48 (s, 1H), 4.08- 3.98 (m, 4.5H), 3.96-3.81(m, 5H), 3.60-3.56 (m, 3H), 3.09-2.86 (m, 4.5H), 1.83- 1.78 (m, 2H).634.3 97.2 (3S,10R)-3- (((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)methyl)- 7-(4- acryloylpiperazin- 1-yl)-10-(2,4-difluorophenyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1306

¹H NMR (400 MHz, CDCl₃) δ 7.86 (s, 1H), 7.23- 7.18 (m, 1H), 7.11-7.01(m, 2H), 6.69-6.62 (m, 1H), 6.44-6.39 (m, 1H), 5.83 (d, J = 14.4 Hz,1H), 5.30-5.26 (m, 1H), 4.48 (s, 1H), 4.08- 3.96 (m, 4.5H), 3.96-3.85(m, 5H), 3.67-3.52 (m, 3H), 3.04-2.86 (m, 4.5H), 1.83- 1.78 (m, 2H).634.3 96.8 (3S,10S)-3- (((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)methyl)- 7-(4- acryloylpiperazin- 1-yl)-10-(2,4-difluorophenyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1307

¹H NMR (400 MHz, CDCl₃) δ: 7.90 (s, 1H), 7.12 (t, J = 11.2 Hz, 1H),6.73- 6.55 (m, 1H), 6.47-6.38 (m, 1H), 5.86-5.81 (m, 1H), 5.46-5.38 (m,1H), 5.14- 4.72 (m, 2H), 4.42-4.37 (m, 2H), 4.17-4.06 (m, 1H), 3.80-3.53(m, 5H), 3.35- 2.83 (m, 10H), 2.41-2.32 (m, 1H), 1.53-1.46 (m, 6H),1.30-1.06 (m, 1H), 0.91- 0.87 (m, 2H). 723.5 69.7 (3S)-7-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4-difluorophenyl)-3- ((4- cyclopropylpiperazin- 1-yl)methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1309

¹H NMR (400 MHz, MeOH-d₄) δ 8.01 (s, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.34(t, J = 9.1 Hz, 1H), 6.80 (dd, J = 16.8, 10.6 Hz, 1H), 6.27 (dd, J =16.8, 2.0 Hz, 1H), 5.80 (dd, J = 10.6, 1.9 Hz, 1H), 4.88-4.58 (m, 4H),4.44 (dd, J = 6.3, 2.8 Hz, 2H), 3.66-3.47 (m, 2H). 621.2 97 8′-(4-acryloylpiperazin- 1-yl- 2,2,3,3,5,5,6,6-d8)- 11′-(5-chloro-2,4-difluorophenyl)- 10′- (trifluoromethyl)- 2′H,4′H,6′H-spiro[oxetane-3,3′- [1,4]thiazepino[2,3- 4-ij]quinazolin]-6′- one 1310

¹H NMR (400 MHz, CDCl₃) δ: 8.12 (s, 1H), 7.92 (d, J = 10.4 Hz, 1H),7.68- 7.62 (m, 1H), 7.35 (d, J = 10.0 Hz, 1H), 7.20 (d, J = 9.6 Hz, 1H),6.75-6.58 (m, 1H), 6.47-6.39 (m, 1H), 5.86-5.81 (m, 1H), 5.44- 5.35 (m,1H), 5.14-4.73 (m, 2H), 4.51-4.16 (m, 2H), 3.79-3.71 (m, 1H), 3.67 (s,3H), 3.55-3.29 (m, 2H), 3.11 (d, J = 16.0 Hz, 1H), 2.81-2.55 (m, 10H),1.55- 1.46 (m, 7H), 0.58-0.40 (m, 4H). 673.4 95 (3S)-7-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-9-chloro-3- ((4-cyclopropylpiperazin- 1-yl)methyl)-10- (1-methyl-1H- indazol-7-yl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1311

¹H NMR (400 MHz, CDCl₃) δ: 7.82 (s, 1H), 7.29-7.28 (m, 1H), 7.10- 7.05(m, 1H), 6.63-6.56 (m, 1H), 6.39-6.35 (m, 1H), 5.79 (d, J = 8.0 Hz, 1H),5.23-5.21 (m, 1H), 4.43- 4.41 (m, 1H), 3.96-3.89 (m, 4H), 3.80-3.78 (m,4H), 3.64-3.50 (m, 2H), 3.02- 2.86 (m, 2H), 2.80-2.78 (m, 2H), 1.78-1.69(m, 2H), 1.61-1.60 (m, 2H), 1.26- 1.24 (m, 1H). 668.2 95.4(3S)-3-(((1S,4S)-2- oxa-5- azabicyclo[2.2.1] heptan-5-yl)methyl)- 7-(4-acryloylpiperazin- 1-yl)-10-(5-chloro- 2,4- difluorophenyl-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1312

¹H NMR (400 MHz, CDCl₃) δ: 7.84-7.82 (m, 1H), 7.26-7.23 (m, 1H), 7.07(t, J = 8.4 Hz, 1H), 6.66-6.53 (m, 1H), 6.41- 6.33 (m, 1H), 5.80-5.75(m, 1H), 5.34-5.32 (m, 1H), 5.05-5.04 (m, 0.5H), 4.83- 4.79 (m, 1H),4.42-4.33 (m, 5.5H), 4.06-4.02 (m, 0.5H), 3.76-3.64 (m, 2H), 3.42- 3.38(m, 1H), 3.28-3.25 (m, 0.5H), 3.01-2.98 (m, 1H), 2.72-2.66 (m, 1H),2.55- 2.35 (m, 5H), 1.82-1.80 (m, 4H), 1.47-1.38 (m, 6H). 724.3 72(3S,10S)-3-((2-oxa- 7- azaspiro[3.5]nonan- 7-yl)methyl)-7- ((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4-difluorophenyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1313

¹H NMR (400 MHz, CDCl₃) δ: 7.83 (s, 1H), 7.30-7.26 (m, 1H), 7.07 (t, J =8.8 Hz, 1H), 6.66-6.50 (m, 1H), 6.41-6.33 (m, 1H), 5.80-5.75 (m, 1H),5.36- 5.34 (m, 1H), 5.03-4.99 (m, 0.5H), 4.79-4.77 (m, 0.5H), 4.67-4.65(m, 0.5H), 4.43- 4.34 (m, 5.5H), 4.09-4.06 (m, 0.5H), 3.76-3.63 (m, 2H),3.45-3.42 (m, 1H), 3.28-3.25 (m, 0.5H), 3.04- 3.00 (m, 1H), 2.91-2.31(m, 6H), 1.90-1.87 (m, 4H), 1.48-1.37 (m, 6H). 724.3 96.4(3S,10R)-3-((2- oxa-7- azaspiro[3.5]nonan- 7-yl)methyl)-7- ((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4-difluorophenyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1314

¹H NMR (400 MHz, CDCl₃) δ 7.84-7.82 (m, 1H), 7.19-7.14 (m, 1H),7.05-6.94 (m, 2H), 6.66- 6.50 (m, 1H), 6.47 (t, J = 14.8 Hz, 1H),5.79-5.75 (m, 1H), 5.36-5.34 (m, 1H), 5.11-4.98 (m, 0.5H), 4.80- 4.68(m, 1H), 4.41-4.33 (m, 5.5H), 4.06-4.03 (m, 0.5H), 3.77-3.64 (m, 2H),3.39- 3.25 (m, 1.5H), 3.00-2.97 (m, 1H), 2.74-2.68 (m, 1H), 2.55-2.36(m, 5H), 1.86- 1.78 (m, 4H), 1.47-1.39 (m, 6H). 690.3 95.8(3S,10S)-3-((2- oxa-7- azaspiro[3.5]nonan- 7-yl)methyl)-7- ((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1315

¹H NMR (400 MHz, CDCl₃) δ: 7.83 (s, 1H), 7.21-7.16 (m, 1H), 7.04- 6.94(m, 2H), 6.66-6.50 (m, 1H), 6.41-6.33 (m, 1H), 5.79-5.75 (m, 1H), 5.32-5.30 (m, 1H), 5.03-4.99 (m, 0.5H), 4.79-4.77 (m, 1H), 4.43-4.34 (m,5.5H), 4.10- 4.06 (m, 0.5H), 3.77-3.63 (m, 2H), 3.40-3.25 (m, 1.5H),3.02-2.98 (m, 1H), 2.74-2.69 (m, 1H), 2.57- 2.34 (m, 5H), 1.86-1.79 (m,4H), 1.47-1.37 (m, 6H). 690.3 96.3 (3S,10R)-3-((2- oxa-7-azaspiro[3.5]nonan- 7-yl)methyl)-7- ((2S,5R)-4- acryloyl-2,5-dimethylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1316

¹H NMR (400 MHz, CDCl₃) δ: 8.05 (s, 1H), 7.30-7.28 (m, 1H), 7.25- 7.23(m, 1H), 7.14-7.10 (m, 1H), 6.66-6.59 (m, 1H), 6.43-6.38 (m, 1H), 5.79-5.76 (m, 1H), 5.45-5.42 (m, 1H), 4.66-4.55 (m, 1H), 4.21-4.15 (m, 2H),3.70- 3.61 (m, 2H), 3.41-3.30 (m, 6H), 2.99-2.94 (m, 1H), 1.62-1.60 (m,4H), 1.48- 1.46 (m, 3H). 611.2 96 (S)-7-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-10-(3-chloro- 4-fluorophenyl)-3-(methoxymethyl)- 9-(trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1317

¹H NMR (400 MHz, CDCl₃) δ 7.86 (s, 1H), 7.24- 7.19 (m, 1H), 7.11-6.98(m, 2H), 6.69-6.60 (m, 1H), 6.45-6.39 (m, 1H), 5.84 (dd, J = 14.0 Hz,2.4 Hz, 1H), 5.47-5.43 (m, 1H), 4.00- 3.85 (m, 8.5H), 3.47-3.42 (m, 1H),3.08-3.03 (m, 1H), 2.89-2.79 (m, 3H), 2.70- 2.48 (m, 8.5H), 1.19 (t, J =9.2 Hz, 3H). 649.2 98.3 (3S,10S)-7-(4- acryloylpiperazin- 1-yl)-10-(2,4-difluorophenyl)-3- ((4-ethylpiperazin- 1-yl)methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1318

¹H NMR (400 MHz, CDCl₃) δ 7.89 (s, 1H), 7.37- 7.19 (m, 1H), 7.10-7.02(m, 2H), 6.65-6.60 (m, 1H), 6.45-6.39 (m, 1H), 5.86- 5.82 (m, 1H),5.43-5.38 (m, 1H), 4.02-3.85 (m, 8H), 3.63-3.56 (m, 2H), 3.36- 3.10 (m,9H), 2.96-2.78 (m, 3H), 1.36 (t, J = 9.2 Hz, 3H). 649.2 99.6(3S,10R)-7-(4- acryloylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-3-((4-ethylpiperazin- 1-yl)methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1319

¹H NMR (400 MHz, CDCl₃) δ: 8.07 (s, 1H), 7.21-7.15 (m, 1H), 7.06- 7.01(m, 1H), 6.98-6.93 (m, 1H), 6.66-6.59 (m, 1H), 6.42 (dd, J = 1.6 Hz,16.8 Hz, 1H), 5.78 (dd, J = 1.2 Hz, 10.4 Hz, 1H), 5.51-5.49 (m, 1H),4.67-4.62 (m, 4H), 4.22-4.19 (m, 2H), 3.82- 3.74 (m, 2H), 3.40-3.30 (m,6H), 3.07-3.03 (m, 1H), 1.61 (d, J = 6.8 Hz, 3H), 1.48 (d, J = 6.8 Hz,3H). 625.3 96.3 (3S,10S)-7- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(2,4- difluorophenyl)-3- ((methoxymethoxy) methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1320

¹H NMR (400 MHz, CDCl₃) δ: 8.07 (s, 1H), 7.20-7.15 (m, 1H), 7.04- 6.94(m, 2H), 6.66-6.59 (m, 1H), 6.42 (dd, J = 1.2 Hz, 16.4 Hz, 1H), 5.78(dd, J = 1.2 Hz, 10.0 Hz, 1H), 5.48- 5.45 (m, 1H), 4.67-4.62 (m, 4H),4.21-4.18 (m, 2H), 3.80-3.78 (m, 2H), 3.39- 3.30 (m, 6H), 3.09-3.05 (m,1H), 1.61 (d, J = 6.8 Hz, 3H), 1.48 (d, J = 6.8 Hz, 3H). 625.3 97.4(3S,10R)-7- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(2,4-difluorophenyl)-3- ((methoxymethoxy) methyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1321

¹H NMR (400 MHz, CDCl₃) δ: 7.80 (s, 1H), 7.21-7.17 (m, 4H), 6.62- 6.54(m, 1H), 6.41-6.31 (m, 1H), 5.82-5.76 (m, 1H), 5.35-5.29 (m, 1H), 3.97-3.73 (m, 9H), 3.47-3.35 (m, 1H), 2.98-2.93 (m, 1H), 2.86-2.46 (m, 10H),0.59- 0.37 (m, 4H). 643.3 99.3 (S)-7-(4- acryloylpiperaizn- 1-yl)-3-((4-cyclopropylpiperazin- 1-yl)methyl)-10- (4-fluorophenyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1322

¹H NMR (400 MHz, CDCl₃) δ: 7.85 (d, J = 10 Hz, 1H), 7.20-7.14 (m, 1H),7.07-6.93 (m, 2H), 6.69- 6.49 (m, 1H), 6.44-6.31 (m, 1H), 5.81-5.75 (m,1H), 5.26-5.17 (m, 1H), 5.09- 4.61 (m, 2H), 4.46-4.31 (m, 2H), 4.14-3.84(m, 2H), 3.77-3.39 (m, 5H), 3.29- 2.79 (m, 5H), 1.80-1.70 (m, 2H),1.50-1.41 (m, 6H). 662.3 96.2 (3S,10S)-3- (((1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl)methyl)- 7-((2S,5R)-4- acryloyl-2,5-dimethylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1323

¹H NMR (400 MHz, CDCl₃) δ: 7.91 (d, J = 16.8 Hz, 1H), 7.20-7.13 (m, 1H),7.04-6.95 (m, 2H), 6.68- 6.49 (m, 1H), 6.43-6.34 (m, 1H), 5.84-5.74 (m,1H), 5.41-5.35 (m, 1H), 5.14- 4.71 (m, 2H), 4.66-4.56 (m, 2H), 4.49-3.88(m, 4H), 3.82-3.46 (m, 6H), 3.19- 3.11 (m, 1H), 2.37-2.26 (m, 2H),2.19-2.14 (m, 1H), 1.61-1.48 (m, 6H). 662.3 96.1 (3S,10R)-3-(((1S,4S)-2-oxa-5- azabicyclo[2.2.1] heptan-5-yl)methyl)- 7-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1324

¹H NMR (400 MHz, CDCl₃) δ: 8.07 (s, 1H), 7.20-7.14 (m, 1H), 7.04- 6.94(m, 2H), 6.66-6.59 (m, 1H), 6.42 (dd, J = 1.6 Hz, 16.4 Hz, 1H), 5.78(dd, J = 1.6 Hz, 10.4 Hz, 1H), 5.37- 5.35 (m, 1H), 4.73-4.60 (m, 2H),4.20-4.17 (m, 2H), 3.39-2.75 (m, 6H), 2.43- 2.31 (m, 6H), 1.61 (d, J =7.2 Hz, 3H), 1.49 (d, J = 7.2 Hz, 3H). 608.3 82.2 (3S,10R)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(2,4-difluorophenyl)-3- ((dimethylamino) methyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1325

¹H NMR (400 MHz, CDCl₃) δ: 8.07 (s, 1H), 7.21-7.15 (m, 1H), 7.06- 6.94(m, 2H), 6.65-6.59 (m, 1H), 6.42 (dd, J = 1.6 Hz, 16.4 Hz, 1H), 5.78(dd, J = 2.0 Hz, 10.4 Hz, 1H), 5.41- 5.38 (m, 1H), 4.77-4.58 (m, 2H),4.21-4.18 (m, 2H), 3.41-2.99 (m, 6H), 2.45- 2.32 (m, 6H), 1.61 (d, J =6.8 Hz, 3H), 1.49 (d, J = 6.8 Hz, 3H). 608.3 81.4 (3S,10S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(2,4-difluorophenyl)-3- ((dimethylamino) methyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1326

¹H NMR (400 MHz, CDCl₃) δ: 7.86-7.83 (m, 1H), 7.19-7.14 (m, 1H),7.05-6.93 (m, 2H), 6.66- 6.50 (m, 1H), 6.37 (t, J = 14.4 Hz, 1H),5.80-5.75 (m, 1H), 5.48-5.47 (m, 1H), 5.07-5.05 (m, 0.5H), 4.83- 4.78(m, 0.5H), 4.69-4.62 (m, 2.5H), 4.47-4.34 (m, 1.5H), 4.10-3.64 (m, 5H),3.35 (s, 3H), 3.27-3.04 (m, 2H), 1.49-1.42 (m, 6H). 625.2 82.3(3S,10S)-7- ((2S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(2,4-difluorophenyl)-3- ((methoxymethoxy) methyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1327

¹H NMR (400 MHz, CDCl₃) δ: 7.85-7.83 (m, 1H), 7.22-7.16 (m, 1H),7.04-6.94 (m, 2H), 6.66- 6.50 (m, 1H), 6.37 (t, J = 14.8 Hz, 1H), 5.77(t, J = 9.2 Hz, 1H), 5.45-5.43 (m, 1H), 5.09-5.03 (m, 0.5H), 4.80- 4.78(m, 0.5H), 4.70-4.62 (m, 2H), 4.44-4.11 (m, 2H), 3.80-3.61 (m, 4H),3.37- 3.20 (m, 4H), 3.09-3.05 (m, 1H), 1.49-1.40 (m, 6H). 625.2 86.3(3S,10R)-7- ((2S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(2,4-difluorophenyl)-3- ((methoxymethoxy) methyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1328

¹H NMR (400 MHz, CDCl₃) δ 7.85-7.83 (m, 1H), 7.22-7.14 (m, 4H),6.67-6.50 (m, 1H), 6.37 (t, J = 15.6 Hz, 1H), 5.77 (t, J = 9.2 Hz, 1H),5.45-5.44 (m, 1H), 5.05-4.80 (m, 1H), 4.67-4.62 (m, 2H), 4.43- 4.07 (m,2H), 3.81-3.62 (m, 4H), 3.35-3.23 (m, 5H), 3.02-2.99 (m, 1H), 1.49- 1.42(m, 6H). 607.2 93.8 (S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-10-(4- fluorophenyl)-3- ((methoxymethoxy) methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1329

¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.22- 7.12 (m, 1H), 7.08-6.92(m, 2H), 6.68-6.56 (m, 1H), 6.46-6.36 (m, 1H), 5.77 (dd, J = 9.2 Hz, 1.6Hz, 1H), 5.40-5.32 (m, 1H), 4.90- 4.54 (m, 2H), 4.18 (d, J = 12.0 Hz,2H), 3.46-3.28 (m, 3.5H), 3.06-2.98 (m, 1H), 2.86-2.76 (m, 3H), 2.70-2.40 (m, 9.5H), 1.62-1.58 (m, 3H), 1.49 (d, J = 6.8 Hz, 3H), 1.12 (t, J= 7.0 Hz, 3H). 677.3 95.4 (3S,10R)-7- ((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-3- ((4-ethylpiperazin-1-yl)methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1330

¹H NMR (400 MHz, CDCl₃) δ: 8.07 (s, 1H), 7.24-7.14 (m, 1H), 7.08- 6.92(m, 2H), 6.68-6.56 (m, 1H), 6.46-6.36 (m, 1H), 5.77 (dd, J = 10.4 Hz,2.0 Hz, 1H), 5.46-5.36 (m, 1H), 4.86-4.46 (m, 2H), 4.24- 4.18 (m, 2H),3.48-3.26 (m, 3.5H), 3.04-2.96 (m, 1H), 2.86-2.70 (m, 3H), 2.62- 2.30(m, 9.5H), 1.62-1.46 (m, 6H), 1.07 (t, J = 7.0 Hz, 3H). 677.3 85(3S,10S)-7- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(2,4-difluorophenyl)-3- ((4-ethylpiperazin- 1-yl)methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1331

¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.28- 7.24 (m, 1H), 7.08 (t, J =8.4 Hz, 1H), 6.66-6.59 (m, 1H), 6.43-6.38 (m, 1H), 5.77 (dd, J = 10.4Hz, 1.6 Hz, 1H), 5.28-5.19 (m, 1H), 4.68- 4.64 (m, 1.5H), 4.45-4.38 (m,1H), 4.18 (m, J = 12.8 Hz, 2H), 3.91-3.88 (m, 1H), 3.63-3.31 (m, 5.5H),3.01- 2.80 (m, 5H), 1.77-1.73 (m, 2H), 1.60 (d, J = 6.8 Hz, 3H), 1.49(d, J = 6.8 Hz, 3H). 696.1 94.5 (3S,10R)-3- (((1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl)methyl)- 7-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4- difluorophenyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1332

¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.29- 7.27 (m, 1H), 7.07 (t, J =8 Hz, 1H), 6.66-6.59 (m, 1H), 6.43-6.38 (m, 1H), 5.79- 5.76 (m, 1H),5.26-5.24 (m, 1H), 4.72-4.60 (m, 2H), 4.41-4.39 (m, 1H), 4.19 (d, J =13.2 Hz, 2H), 3.91-3.87 (m, 1H), 3.62-3.32 (m, 5.5H), 3.01-2.83 (m,4.5H), 1.75-1.66 (m, 2H), 1.61 (d, J = 6.8 Hz, 3H), 1.47 (d, J = 7.2 Hz,3H). 696.1 87 (3S,10S)-3- (((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)methyl)- 7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-chloro- 2,4- difluorophenyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1333

¹H NMR (400 MHz, CDCl₃) δ: 8.05 (s, 1H), 7.21-7.18 (m, 4H), 6.66- 6.59(m, 1H), 6.40 (dd, J = 17.2 Hz, 1.6 Hz, 1H), 5.77 (dd, J = 10.8 Hz, 1.6Hz, 1H), 5.36-5.35 (m, 1H), 4.72-4.55 (m, 1H), 4.20- 4.17 (m, 2H),3.38-3.29 (m, 3H), 2.97-2.94 (m, 1H), 2.83-2.47 (m, 9H), 1.60- 1.59 (m,6H), 1.49 (d, J = 7.2 Hz, 3H), 0.69-0.20 (m, 4H). 671.5 61(S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-3-((4-cyclopropylpiperazin- 1-yl)methyl)-10- (4-fluorophenyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1334

¹H NMR (400 MHz, CDCl₃) δ: 7.84 (d, J = 4.0 Hz, 1H), 7.30-7.28 (m, 1H),7.08 (t, J = 8.8 Hz, 1H), 6.67-6.50 (m, 1H), 6.41- 6.33 (m, 1H),5.80-5.76 (m, 1H), 5.25-5.17 (m, 1H), 5.08-5.01 (m, 0.5H), 4.82- 4.66(m, 1H), 4.44-4.35 (m, 2.5H), 4.16-3.91 (m, 2H), 3.77-3.49 (m, 5H),3.27- 2.88 (m, 5H), 1.77-1.74 (m, 2H), 1.52-1.34 (m, 6H). 696.3 80(3S,10R)-3- (((1S,4S)-2-oxa-5- azabicyclo[2.2.1] heptan-5-yl)methyl)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4-difluorophenyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1335

¹H NMR (400 MHz, CDCl₃) δ: 7.84 (d, J = 10.0 Hz, 1H), 7.23-7.22 (m, 1H),7.09-7.05 (m, 1H), 6.67- 6.51 (m, 1H), 6.41-6.34 (m, 1H), 5.80-5.76 (m,1H), 5.28-5.21 (m, 1H), 5.06- 5.05 (m, 0.5H), 4.78-4.65 (m, 1H),4.40-4.33 (m, 2.5H), 4.09-3.88 (m, 2H), 3.75-3.43 (m, 5H), 3.26- 2.81(m, 5H), 1.75-1.742 (m, 2H), 1.52-1.43 (m, 6H). 696.3 29.7 (3S,10S)-3-(((1S,4S)-2-oxa-5- azabicyclo[2.2.1] heptan-5-yl)methyl)- 7-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4-difluorophenyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1336

¹H NMR (400 MHz, CDCl₃) δ: 8.05 (s, 1H), 7.30-7.23 (m, 2H), 7.11- 7.10(m, 1H), 6.65-6.59 (m, 1H), 6.43-6.38 (m, 1H), 5.79-5.76 (m, 1H), 4.74-4.60 (m, 4H), 4.17-4.15 (m, 2H), 3.76-3.66 (m, 4H), 3.37-3.11 (m, 5H),2.80- 2.43 (m, 4H), 1.58-1.54 (m, 6H). 666.1 85.5 (R)-8-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin- 1-yl)-11-(3-chloro- 4-fluorophenyl)-3-morpholino-10- (trifluoromethyl)- 3,4-dihydro- 2H,6H-[1,4]thiazepino[2,3- 4-ij]quinazolin-6- one 1337

¹H NMR (400 MHz, CDCl₃) δ: 7.80 (s, 1H), 7.28-7.26 (m, 1H), 7.08- 7.04(m, 1H), 6.62-6.56 (m, 1H), 6.39-6.34 (m, 1H), 5.80-5.77 (m, 1H), 5.41-5.37 (m, 1H), 3.94-3.79 (m, 8.5H), 3.48-3.44 (m, 1H), 3.02-2.98 (m, 1H),2.79- 2.74 (m, 3H), 2.54-2.36 (m, 8.5H), 1.07 (t, J = 6.8 Hz, 3H). 683.396.7 (3S,10S)-7-(4- acryloylpiperazin- 1-yl)-10-(5-chloro- 2,4-difluorophenyl)-3- ((4-ethylpiperazin- 1-yl)methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1338

¹H NMR (400 MHz, CDCl₃) δ: 7.80 (s, 1H), 7.29-7.26 (m, 1H), 7.09- 7.04(m, 1H), 6.62-6.55 (m, 1H), 6.39-6.34 (m, 1H), 5.79-5.76 (m, 1H), 5.37-5.33 (m, 1H), 3.94-3.78 (m, 8.5H), 3.49-3.45 (m, 1H), 3.02-2.98 (m, 1H),2.83- 2.77 (m, 3H), 2.56-2.36 (m, 8.5H), 1.09-1.05 (t, J = 6.8 Hz, 3H).683.3 99 (3S,10R)-7-(4- acryloylpiperazin- 1-yl)-10-(5-chloro- 2,4-difluorophenyl)-3- ((4-ethylpiperazin- 1-yl)methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1339

¹H NMR (400 MHz, CDCl₃) δ: 8.06 (s, 1H), 7.28-7.24 (m, 1H), 7.07 (t, J =8.8 Hz, 1H), 6.66-6.59 (m, 1H), 6.43-6.38 (m, 1H), 5.77 (dd, J = 10.0Hz, 2.0 Hz, 1H), 5.39-5.35 (m, 1H), 4.71-4.59 (m, 1H), 4.20- 4.15 (m,2H), 3.48-3.44 (m, 1H), 3.37-3.29 (m, 2H), 3.03-2.99 (m, 1H), 2.82- 2.72(m, 3H), 2.55-2.32 (m, 9H), 1.59-1.58 (d, J = 6.8 Hz, 4H), 1.50-1.49 (d,J = 6.8 Hz, 3H), 1.09-1.05 (t, J = 7.2 Hz, 3H). 711.2 68.7 (3S,10R)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4-dichlorophenyl)-3- ((4-ethylpiperazin- 1-yl)methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1340

¹H NMR (400 MHz, CDCl₃) δ: 8.06 (s, 1H), 7.29-7.26 (m, 1H), 7.07 (t, J =8.4 Hz, 1H), 6.66-6.59 (m, 1H), 6.43-6.38 (m, 1H), 5.79-5.76 (m, 1H),5.42- 5.39 (m, 1H), 4.83-4.53 (m, 1H), 4.20-4.15 (m, 2H), 3.46-3.29 (m,1H), 3.02- 2.99 (m, 1H), 2.80-2.72 (m, 3H), 2.57-2.35 (m, 9H), 1.60-1.59(d, J = 6.8 Hz, 4H), 1.49-1.47 (d, J = 7.2 Hz, 3H), 1.11-1.07 (t, J =6.8 Hz, 3H). 711.2 89.4 (3S,10S)-7- ((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4- difluorophenyl)-3-((4-ethylpiperazin- 1-yl)methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1341

¹H NMR (400 MHz, CDCl₃) δ: 7.81 (s, 1H), 7.27 (m, 1H), 7.10-7.06 (t, J =8.8 Hz, 1H), 6.63-6.56 (m, 1H), 6.37 (dd, J = 1.6 Hz, 16.8 Hz, 1H), 5.79(dd, J = 1.6 Hz, 10.4 Hz, 1H), 5.12- 5.10 (m, 1H), 4.42 (s, 1H),3.96-3.90 (m, 4H), 3.82- 3.79 (m, 5H), 3.64-3.52 (m, 3H), 3.02-2.89 (m,5H), 1.78-1.74 (m, 2H). 668.1 97.4 (3S,10R)-3- (((1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl)methyl)- 7-(4- acryloylpiperazin-1-yl)-10-(5-chloro- 2,4- difluorophenyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1342

¹H NMR (400 MHz, CDCl₃) δ: 7.82 (s, 1H), 7.29-7.26 (m, 1H), 7.07 (t, J =8.8 Hz, 1H), 6.63-6.56 (m, 1H), 6.37 (dd, J = 1.6 Hz, 16.8 Hz, 1H), 5.79(dd, J = 1.6 Hz, 10.4 Hz, 1H), 5.26-5.25 (m, 1H), 4.41- 4.39 (m, 1H),3.97-3.87 (m, 4H), 3.86-3.80 (m, 5H), 3.62-3.50 (m, 3H), 3.01- 2.84 (m,5H), 1.76-1.70 (m, 2H). 668.1 44.1 (3S,10S)-3- (((1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl)methyl)- 7-(4- acryloylpiperazin-1-yl)-10-(5-chloro- 2,4- difluorophenyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1343

¹H NMR (400 MHz, MeOH-d₄) δ: 7.89 (s, 1H), 7.43 (ddd, J = 10.5, 8.4, 6.2Hz, 1H), 7.30-7.13 (m, 2H), 6.91 (J_(HF) = 73.1 Hz, 1H), 6.83 (dd, J =16.7, 10.6 Hz, 1H), 6.28 (dd, J = 16.6, 2.0 Hz, 1H), 5.80 (dd, J = 10.5,2.0 Hz, 1H), 5.40-5.30 (m, 1H), 4.78-4.51 (m, 2H), 4.37 (d, J = 13.6 Hz,1H), 4.25 (dt, J = 13.5, 2.2 Hz, 1H), 3.75 (td, J = 9.1, 4.9 Hz, 1H),3.67-3.50 (m, 3H), 3.49-3.41 (m, 2H), 3.40 (d, J = 7.0 Hz, 3H),3.38-3.34 (m, 1H), 3.11 (dt, J = 13.5, 2.6 Hz, 1H), 1.54 (d, J = 6.9 Hz,3H), 1.39 (d, J = 7.0 Hz, 3H). 609.06 96 (S)-7-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-9-chloro-10- (3- (difluoromethoxy)-4-fluorophenyl)-3- (methoxymethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1343a

¹H NMR (400 MHz, MeOH-d₄) δ 7.90 (s, 1H), 7.42-7.26 (m, 1H), 7.22- 7.10(m, 2H), 6.83 (dd, J = 16.7, 10.6 Hz, 1H), 6.28 (dd, J = 16.7, 2.0 Hz,1H), 5.41-5.31 (m, 1H), 4.80- 4.52 (m, 2H), 4.44-4.31 (m, 1H), 4.25 (d,J = 13.5 Hz, 1H), 3.79-3.64 (m, 1H), 3.63-3.50 (m, 2H), 3.49- 3.41 (m,2H), 3.39 (s, 3H), 3.38-3.33 (m, 1H), 3.15 (td, J = 13.2, 3.0 Hz, 1H),1.54 (dd, J = 7.0, 2.6 Hz, 3H), 1.40 (dd, J = 7.0, 3.2 Hz, 3H). 561.296.8 (3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-9-chloro-10- (2,4- difluorophenyl)-3- (methoxymethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1344

¹H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H), 7.21- 7.15 (m, 4H), 6.66-6.59(m, 1H), 6.40 (dd, J = 16.8 Hz, J = 2 Hz, 1H), 5.76 (dd, J = 8.4 Hz, J =2 Hz, 1H), 5.37- 5.34 (m, 1H), 4.67-4.63 (m, 2H), 4.20-4.15 (m, 2H),3.42-3.29 (m, 3H), 2.96- 2.92 (m, 1H), 2.83-2.77 (m, 3H), 2.54-2.37 (m,9H), 1.60 (d, J = 6.8 Hz, 3H), 1.50 (d, J = 6.8 Hz, 3H), 1.07 (t, J =7.2 Hz, 3H). 659.4 96 (S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-3-((4- ethylpiperazin-1- yl)methyl)-10-(4- fluorophenyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1345

¹H NMR (400 MHz, CDCl₃) δ: 7.80 (s, 1H), 7.32-7.30 (m, 1H), 7.28- 7.23(m, 1H), 7.14-7.09 (m, 1H), 6.62-6.56 (m, 1H), 6.39-6.34 (m, 1H), 5.78(dd, J = 10.4 Hz, 2.0 Hz, 1H), 5.44-5.39 (m, 1H), 3.80- 3.70 (m, 8H),3.68-3.63 (m, 2H), 3.41-3.33 (m, 4H), 2.99-2.94 (m, 1H). 583.3 90(S)-7-(4- acryloylpiperazin- 1-yl)-10-(3-chloro- 4-fluorophenyl)-3-(methoxymethyl)- 9-(trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1346

¹H NMR (400 MHz, CDCl₃) δ: 8.07 (s, 1H), 7.18 (q, J = 8.0 Hz, 1H),7.05-6.94 (m, 2H), 6.62 (dd, J = 10.4 Hz, J = 16.4 Hz, 1H), 6.40 (dd, J= 2.0 Hz, J = 16.8 Hz, 1H), 5.77 (dd, J = 1.6 Hz, J = 10.4 Hz, 1H),5.37-5.34 (m, 1H), 4.81-4.53 (m, 2H), 4.18 (d, J = 13.2 Hz, 2H),3.46-3.40 (m, 1H), 3.37- 3.30 (m, 2H), 3.02 (d, J = 12.8 Hz, 1H),2.82-2.53 (m, 9H), 1.59 (d, J = 6.8 Hz, 5H), 1.49 (d, J = 6.8 Hz, 3H),0.64-0.26 (m, 4H). 689.2 96.9 (3S,10R)-7- ((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-3-((4- cyclopropylpiperazin- 1-yl)methyl)-10-(2,4- difluorophenyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1347

¹H NMR (400 MHz, CDCl₃) δ: 8.07 (s, 1H), 7.17 (q, J = 8.0 Hz, 1H),7.06-6.94 (m, 2H), 6.62 (dd, J = 10.4 Hz, J = 16.8 Hz, 1H), 6.40 (dd, J= 1.6 Hz, J = 16.4 Hz, 1H), 5.77 (dd, J = 1.6 Hz, J = 10.4 Hz, 1H),5.44-5.37 (m, 1H), 4.73-4.56 (m, 2H), 4.21-4.16 (m, 2H), 3.39- 3.32 (m,3H), 3.03 (d, J = 13.6 Hz, 2H), 2.83-2.31 (m, 8H), 1.60 (d, J = 6.8 Hz,5H), 1.49 (d, J = 7.2 Hz, 3H), 1.08-0.27 (m, 4H). 689.2 89.7 (3S,10S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-3-((4-cyclopropylpiperazin- 1-yl)methyl)-10- (2,4- difluorophenyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1348

¹H NMR (400 MHz, CDCl₃) δ: 8.06 (s, 1H), 7.28-7.24 (m, 1H), 7.07 (t, J =8.8 Hz, H), 6.62 (dd, J = 10.8 Hz, J = 16.8 Hz, 1H), 6.40 (dd, J = 1.6Hz, J = 16.8 Hz, 1H), 5.77 (dd, J = 2.0 Hz, J = 10.4 Hz, 1H), 5.38-5.35(m, 1H), 4.78- 4.55 (m, 2H), 4.19-4.16 (m, 2H), 3.52-3.44 (m, 1H),3.37-3.31 (m, 2H), 3.04- 3.00 (m, 1H), 2.80-2.55 (m, 9H), 1.58 (d, J =6.8 Hz, 5H), 1.49 (d, J = 6.8 Hz, 3H), 0.64-0.35 (m, 4H). 723.2 94.4(3S,10R)-7- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-chloro- 2,4- difluorophenyl)-3- ((4- cyclopropylpiperazin-1-yl)methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1349

¹H NMR (400 MHz, CDCl₃) δ: 8.06 (s, 1H), 7.29-7.26 (m, 1H), 7.07 (t, J =8.4 Hz, 1H), 6.62 (dd, J = 10.8 Hz, J = 16.8 Hz, 1H), 6.40 (dd, J = 2.0Hz, J = 16.8 Hz, 1H), 5.77 (dd, J = 2.0 Hz, J = 10.4 Hz, 1H), 5.41-5.39(m, 1H), 4.74- 4.56 (m, 2H), 4.20-4.15 (m, 2H), 3.47-3.31 (m, 3H), 3.02(d, J = 12.0 Hz, 1H), 2.77-2.50 (m, 9H), 1.59 (d, J = 7.2 Hz, 5H), 1.48(d, J = 6.8 Hz, 3H), 0.87-0.36 (m, 4H). 723.2 86.9 (3S,10S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4-difluorophenyl)-3- ((4- cyclopropylpiperazin- 1-yl)methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1350

¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 1H), 7.21-7.15 (m, 4H), 6.63- 6.56(m, 1H), 6.39-3.34 (m, 1H), 5.78 (dd, J = 10.4 Hz, 1.6 Hz, 1H),5.34-5.18 (m, 1H), 4.43-4.40 (m, 1H), 3.95-3.80 (m, 10H), 3.62- 3.45 (m,3H), 2.94-2.86 (m, 4H), 1.75-1.71 (m, 2H). 616.1 81.3 (S)-3-(((1S,4S)-2-oxa-5- azabicyclo[2.2.1] heptan-5-yl)methyl)- 7-(4- acryloylpiperazin-1-yl)-10-(4- fluorophenyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1351

¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, J = 6.4 Hz, 1H), 7.25-7.17 (m, 4H),6.67-6.50 (m, 1H), 6.41- 6.33 (m, 1H), 5.80-5.75 (m, 1H), 5.25-5.17 (m,1H), 5.09-4.65 (m, 2H), 4.43- 4.35 (m, 2.5H), 4.12-4.05 (m, 0.5H),3.95-3.87 (m, 1H), 3.76-3.39 (m, 6H) 3.28-2.93 (m, 5H), 1.82- 1.70 (m,2H), 1.49-1.40 (m, 6H). 644.4 64.8 (S)-3-(((1S,4S)-2- oxa-5-azabicyclo[2.2.1] heptan-5-yl)methyl)- 7-((2S,5R)-4- acryloyl-2,5-dimethylpiperazin- 1-yl)-10-(4- fluorophenyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1352

¹H NMR (400 MHz, CDCl₃) δ: 8.06 (s, 1H), 7.21-7.15 (m, 4H), 6.66- 6.59(m, 1H), 6.43-6.38 (m, 1H), 5.78-5.75 (m, 1H), 5.27-5.18 (m, 1H), 4.68-4.64 (m, 2H), 4.44-4.41 (m, 1H), 4.20-4.17 (m, 2H), 3.91-3.88 (m, 1H),3.62- 3.31 (m, 5H) 2.95-2.86 (m, 5H), 1.76-1.71 (m, 2H), 1.62-1.60 (m,3H), 1.49- 1.47 (m, 3H). 644.4 96.1 (S)-3-(((1S,4S)-2- oxa-5-azabicyclo[2.2.1] heptan-5-yl)methyl)- 7-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-10-(4- fluorophenyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1353

¹H NMR (400 MHz, CDCl₃) δ: 8.11 (s, 1H), 7.34-7.28 (m, 2H), 7.16- 7.14(m, 1H), 6.72-6.63 (m, 1H), 6.49-6.43 (m, 1H), 5.85-5.81 (m, 1H), 4.81-4.65 (m, 6H), 4.41-4.38 (m, 2H), 4.22-4.18 (m, 2H), 3.44-3.41 (m, 4H),1.60- 1.58 (m, 6H). 623.3 96.4 8′-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-11′-(3-chloro- 4-fluorophenyl)- 10′-(trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]-6′- one 1354

¹H NMR (400 MHz, CDCl₃) δ: 7.79 (s, 1H), 7.31-7.24 (m, 2H), 7.11- 7.08(m, 1H), 6.66-6.51 (m, 1H), 6.42-6.34 (m, 1H), 5.80-5.76 (m, 1H), 5.09-4.67 (m, 5.5H), 4.41-4.29 (m, 3H), 3.91-3.67 (m, 3H), 3.44-3.35 (m,2.5H), 1.39- 1.32 (m, 6H). 623.3 96 8′-((2S,5R)-4- acryloyl-2,5-dimethylpiperazin- 1-yl)-11′-(3-chloro- 4-fluorophenyl)- 10′-(trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]-6′- one 1355

¹H NMR (400 MHz, CDCl₃) δ: 7.80 (s, 1H), 7.29-7.25 (m, 1H), 7.07 (t, J =8.8 Hz, 1H), 6.59 (dd, J = 10.4 Hz, 16.8 Hz, 1H), 6.36 (dd, J = 1.6 Hz,16.8 Hz, 1H), 5.78 (dd, J = 1.6 Hz, 10.4 Hz, 1H), 5.36- 5.33 (m, 1H),3.94-3.91 (m, 3H), 3.82-3.79 (m, 5H), 3.48 (d, J = 11.2 Hz, 1H), 3.02(d, J = 13.2 Hz, 1H), 2.80-2.54 (m, 10H), 1.39- 1.25 (m, 1H), 0.55-0.36(m, 4H). 695.4 99.2 (3S,10R)-7-(4- acryloylpiperazin-1-yl)-10-(5-chloro- 2,4- difluorophenyl)-3- ((4- cyclopropylpiperazin-1-yl)methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1356

¹H NMR (400 MHz, CDCl₃) δ: 7.81 (s, 1H), 7.28-7.26 (m, 1H), 7.07 (t, J =8.8 Hz, 1H), 6.59 (dd, J = 10.4 Hz, 16.8 Hz, 1H), 6.37 (dd, J = 1.6 Hz,16.8 Hz, 1H), 5.78 (dd, J = 1.6 Hz, 10.4 Hz, 1H), 5.41- 5.37 (m, 1H),3.98-3.91 (m, 3H), 3.82-3.79 (m, 5H), 3.49-3.40 (m, 1H), 3.02 (d, J =13.6 Hz, 1H), 2.86-2.41 (m, 10H), 1.31-1.17 (m, 1H), 0.71-0.25 (m, 4H).695.4 92.8 (3S,10S)-7-(4- acryloylpiperazin- 1-yl)-10-(5-chloro- 2,4-difluorophenyl)-3- ((4- cyclopropylpiperazin- 1-yl)methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1357a

¹H NMR (400 MHz, MeOH-d₄) δ 7.97 (s, 1H), 7.50 (dd, J = 15.3, 7.8 Hz,1H), 7.34 (td, J = 9.1, 3.3 Hz, 1H), 6.91-6.72 (m, 1H), 6.34-6.22 (m,1H), 5.81 (ddd, J = 9.8, 7.3, 1.9 Hz, 1H), 4.88-4.59 (m, 3H), 4.45 (d, J= 6.3 Hz, 2H), 3.99-3.71 (m, 1H), 3.71-3.46 (m, 2H), 1.43 (dd, J = 16.2,6.6 Hz, 3H), 1.38-1.30 (m, 3H). 641.2 74.3 8′-((2S,5R)-4- acryloyl-2,5-dimethylpiperazin- 1-yl)-11′-(5-chloro- 2,4- difluorophenyl)- 10′-(trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3-4-ij]quinazolin-6′- one 1357

¹H NMR (400 MHz, CDCl₃) δ: 7.81 (s, 1H), 7.30-7.23 (m, 2H), 7.11- 7.09(m, 1H), 6.62-6.55 (m, 1H), 6.39-6.35 (m, 1H), 5.82-5.78 (m, 1H), 5.14-4.64 (m, 3.5H), 4.36-4.33 (m, 2H), 4.00-3.73 (m, 8.5H), 3.42-3.39 (m,2H). 595.1 92.4 8′-(4- acryloylpiperazin- 1-yl)-11′-(3-chloro-4-fluorophenyl)- 10′- (trifluoromethyl)- 2′H,4′H,6′H-spiro[oxetane-3,3′- [1,4]thiazepino[2,3- 4-ij]quinazolin]-6′- one 1358

¹H NMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.24- 7.15 (m, 4H), 6.63-6.56(m, 1H), 6.39 (d, J = 16.4 Hz, 1H), 5.80 (d, J = 10.4 Hz, 1H), 5.46-5.45(m, 1H), 4.67-4.62 (m, 2H), 4.02- 3.95 (m, 3H), 3.81-3.79 (m, 7H),3.35-3.33 (m, 4H), 3.01-2.98 (m, 1H). 579.2 96.3 (S)-7-(4-acryloylpiperazin- 1-yl)-10-(4- fluorophenyl)-3- ((methoxymethoxy)methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1359

¹H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H), 7.32- 7.23 (m, 2H), 7.13-7.10(m, 1H), 6.65-6.59 (m, 1H), 6.43 (dd, J = 12.8 Hz, 2 Hz, 1H), 5.79 (dd,J = 8.4 Hz, 1.6 Hz, 1H), 5.48-5.46 (m, 1H), 4.68-4.62 (m, 3H), 4.20-4.17(m, 2H), 3.83- 3.77 (m, 2H), 3.39-3.30 (m, 6H), 3.03-2.98 (m, 1H),1.62-1.60 (m, 4H), 1.48- 1.46 (m, 3H). 641.1 74.6 (S)-7-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(3-chloro- 4-fluorophenyl)-3-((methoxymethoxy) methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1360

¹H NMR (400 MHz, CDCl₃) δ: 7.52 (s, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.10(t, J = 8.8 Hz, 1H), 6.66-6.50 (m, 1H), 6.37 (t, J = 14.4 Hz, 1H),5.79-5.75 (m, 1H), 5.45-5.41 (m, 1H), 4.98- 4.86 (m, 1H), 4.72-4.71 (m,0.5H), 4.44-4.36 (m, 0.5H), 4.33-4.29 (m, 0.5H), 4.23- 4.19 (m, 0.5H),3.99-3.96 (m, 0.5H), 3.83-3.77 (m, 1H), 3.72-3.65 (m, 1H), 3.49-3.35 (m,1.5H), 3.06- 3.02 (m, 1H), 2.84-2.46 (m, 10H), 1.39-1.22 (m, 7H),0.69-0.27 (m, 4H). 689.2 92.8 (3S,10R)-7- ((2S,5R)-4- acryloyl-2,5-dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4- difluorophenyl)-3- ((4-cyclopropylpiperazin- 1-yl)methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1361

¹H NMR (400 MHz, CDCl₃) δ: 7.53 (s, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.09(t, J = 8.4 Hz, 1H), 6.63-6.51 (m, 1H), 6.37 (t, J = 22.0 Hz, 1H),5.79-5.75 (m, 1H), 5.48-5.40 (m, 1H), 5.00 (m, 0.5H), 4.84 (m, 0.5H),4.71- 4.70 (m, 0.5H), 4.38 (m, 0.5H), 4.31 (m, 0.5H), 4.22 (m, 0.5H),3.99-3.96 (m, 0.5H), 3.82-3.65 (m, 2H), 3.49-3.48 (m, 0.5H), 3.36- 3.33(m, 1H), 3.07-3.04 (m, 1H), 2.79-2.45 (m, 10H), 1.45-1.22 (m, 7H), 0.97-0.13 (m, 4H). 689.2 29.8 (3S,10S)-7- ((2S,5R)-4- acryloyl-2,5-dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4- difluorophenyl)-3- ((4-cyclopropylpiperazin- 1-yl)methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1361a

¹H NMR (400 MHz, MeOH-d₄) δ 8.18 (s, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.37(t, J = 9.1 Hz, 1H), 6.85 (dd, J = 16.7, 10.6 Hz, 1H), 6.31 (dd, J =16.7, 2.0 Hz, 1H), 5.82 (dd, J = 10.6, 2.0 Hz, 1H), 4.88-4.58 (m, 4H),4.46 (dd, J = 6.4, 2.4 Hz, 2H), 4.27 (d, J = 13.5 Hz, 2H), 3.58 (d, J =6.6 Hz, 2H), 3.46 (dt, J = 13.7, 4.5 Hz, 2H), 1.59-1.46 (m, 6H). 641.193.3 (R)-8′-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11′-(5-chloro- 2,4- difluorophenyl)- 10′- (trifluoromethyl)-2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]-6′- one 1361b

¹H NMR (400 MHz, MeOH-d₄) δ 8.16 (s, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.34(t, J = 9.1 Hz, 1H), 6.83 (dd, J = 16.7, 10.6 Hz, 1H), 6.29 (dd, J =16.6, 2.0 Hz, 1H), 5.80 (dd, J = 10.6, 2.0 Hz, 1H), 4.88-4.54 (m, 4H),4.44 (dd, J = 6.4, 2.4 Hz, 2H), 4.25 (d, J = 13.5 Hz, 2H), 3.56 (d, J =6.6 Hz, 2H), 3.44 (dt, J = 13.9, 4.5 Hz, 2H), 1.55-1.41 (m, 6H). 641.171.4 (S)-8′-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11′-(5-chloro- 2,4- difluorophenyl)- 10′- (trifluoromethyl)-2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3,4-ij]quinazolin-6′- one 1362

¹H NMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.32- 7.23 (m, 2H), 7.14-7.11(m, 1H), 6.59 (dd, J = 10.4 Hz, 16.8 Hz, 1H), 6.39 (dd, J = 1.6 Hz, 16.8Hz, 1H), 5.80 (dd, J = 1.2 Hz, 10.0 Hz, 1H), 5.47-5.43 (m, 1H),4.68-4.62 (m, 2H), 4.05- 3.94 (m, 3H), 3.81-3.78 (m, 7H), 3.37-3.35 (m,4H), 3.02-2.99 (m, 1H). 613.02 96.2 (S)-7-(4- acryloylpiperazin-1-yl)-10-(3-chloro- 4-fluorophenyl)-3- ((methoxymethoxy) methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1363

¹H NMR (400 MHz, CDCl₃) δ 7.84-7.82 (m, 1H), 7.34-7.23 (m, 2H),7.15-7.09 (m, 1H), 6.66- 6.50 (m, 1H), 6.41-6.33 (m, 1H), 5.80-5.75 (m,1H), 5.45-5.44 (m, 1H), 5.06- 4.80 (m, 1H), 4.68-4.62 (m, 2H), 4.43-4.05(m, 2H), 3.81-3.62 (m, 4H), 3.37- 3.22 (m, 5H), 3.03-3.00 (m, 1H),1.49-1.41 (m, 6H). 641.08 92.1 (S)-7-((2S,5R)-4- acryloyl-2,5-dimethylpiperazin- 1-yl)-10-(3-chloro- 4-fluorophenyl)-3-((methoxymethoxy) methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1364

¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 1H), 7.30- 7.26 (m, 1H), 7.07 (t, J =8.8 Hz, 1H), 6.59 (dd, J = 10.4 Hz, 16.8 Hz, 1H), 6.37 (dd, J = 1.6 Hz,16.8 Hz, 1H), 5.79 (dd, J = 1.2 Hz, 10.4 Hz, 1H), 5.48-5.44 (m, 1H),4.68-4.63 (m, 2H), 3.97- 3.82 (m, 3H), 3.80-3.78 (m, 7H), 3.42-3.36 (m,4H), 3.0-3.05 (m, 1H). 631.1 98 (3S,10R)-7-(4- acryloylpiperazin-1-yl)-10-(5-chloro- 2,4- dichlorophenyl)-3- ((methoxymethoxy) methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1365

¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 1H), 7.28- 7.25 (m, 1H), 7.06 (t, J =8.8 Hz, 1H), 6.59 (dd, J = 10.4 Hz, 16.8 Hz, 1H), 6.37 (dd, J = 1.6 Hz,16.8 Hz, 1H), 5.79 (dd, J = 1.6 Hz, 10.4 Hz, 1H), 5.52-5.47 (m, 1H),4.67-4.62 (m, 2H), 3.97- 3.84 (m, 3H), 3.81-3.76 (m, 7H), 3.42-3.35 (m,4H), 3.07-3.04 (m, 1H). 631.1 83.7 (3S,10S)-7-(4- acryloylpiperazin-1-yl)-10-(5-chloro- 2,4- dichlorophenyl)-3- ((methoxymethoxy) methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1366

¹H NMR (400 MHz, MeOH-d₄) δ 8.13 (s, 1H), 7.34-7.19 (m, 4H), 5.38- 5.30(m, 1H), 4.81-4.57 (br s, 2H), 4.39-4.22 (m, 2H), 3.73 (t, J = 9.2 Hz,1H), 3.60 (dd, J = 9.2, 4.8 Hz, 1H), 3.49 (dd, J = 9.2, 4.8 Hz, 1H),1H), 3.39 (s, 3H), 3.45-3.33 (m, 2H), 3.09 (dd, J = 13.6, 2.9 Hz, 1H),1.57 (d, J = 7.0 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H). 580.3 96.8(S)-7-((3S,5R)-4- (Acryloyl)-d₃)-3,5 dimethylpiperazin- 1-yl)-10-(4-fluorophenyl)-3- (methoxymethyl)- 9-(trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1366a

¹H NMR (400 MHz, MeOH-d₄) δ 8.22 (s, 1H), 8.16 (s, 1H), 7.18 (dd, J =8.0, 4.8 Hz, 1H), 6.98 (dd, J = 9.7, 7.9 Hz, 1H), 6.85 (dd, J = 16.7,10.6 Hz, 1H), 6.30 (dd, J = 16.6, 2.0 Hz, 1H), 5.81 (dd, J = 10.6, 2.0Hz, 1H), 5.41-5.31 (m, 1H), 4.84-4.55 (m, 2H), 4.39 (d, J = 13.6 Hz,1H), 4.30 (d, J = 13.6 Hz, 1H), 3.74-3.60 (m, 3H), 3.56 (s, 3H), 3.55-3.37 (m, 3H), 3.36 (s, 3H), 3.35-3.33 (m, 1H), 3.15 (dd, J = 13.7, 3.0Hz, 1H), 1.60 (d, J = 6.9 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H). 631.3 46.8(3S,10S)-7- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(4-fluoro- 1-methyl-1H- indazol-7-yl)-3- (methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1367

¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 1H), 7.21- 7.15 (m, 1H), 7.04-6.94(m, 2H), 6.62-6.55 (m, 1H), 6.39 (dd, J = 17.2 Hz, 2.0 Hz, 1H), 5.79(dd, J = 10.4 Hz, 2.0 Hz, 1H), 5.47-5.42 (m, 1H), 4.67-4.62 (m, 2H),4.05-3.97 (m, 3H), 3.80- 3.78 (m, 7H), 3.40-3.35 (m, 1H), 3.34 (s, 3H),3.07 (dd, J = 13.6 Hz, 2.8 Hz, 1H). 597.2 92.4 (3S,10R)-7-(4-acryloylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-3- ((methoxymethoxy)methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1368

¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 1H), 7.20- 7.15 (m, 1H), 7.05-6.93(m, 2H), 6.62-6.56 (m, 1H), 6.39 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.79(dd, J = 10.8 Hz, 2.0 Hz, 1H), 5.51-5.46 (m, 1H), 4.67-4.62 (m, 2H),4.04-3.91 (m, 3H), 3.82- 3.74 (m, 7H), 3.39-3.36 (m, 4H), 3.05 (dd, J =13.6 Hz, 2.8 Hz, 1H). 597.2 92.4 (3S,10S)-7-(4- acryloylpiperazin-1-yl)-10-(2,4- difluorophenyl)-3- ((methoxymethoxy) methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1369

¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.29- 7.26 (m, 1H), 7.08-7.04(m, 1H), 6.65-6.59 (m, 1H), 6.43 (dd, J = 16.8 Hz, 2 Hz, 1H), 5.79 (dd,J = 10 Hz, 1.6 Hz, 1H), 5.52-5.48 (m, 1H), 4.68-4.62 (m, 3H), 4.21- 4.17(m, 2H), 3.81-3.76 (m, 2H), 3.42-3.30 (m, 6H), 3.08-3.04 (m, 1H), 1.62-1.57 (m, 4H), 1.47 (d, J = 6.8 Hz, 3H). 659.3 64.6 (3S,10S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4-dichlorophenyl)-3- ((methoxymethoxy) methyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1370

¹H NMR (400 MHz, CDCl₃) δ: 8.06 (s, 1H), 7.29-7.26 (m, 1H), 7.10- 7.05(m, 1H), 6.65-6.58 (m, 1H), 6.43 (dd, J = 16.4 Hz, 2 Hz, 1H), 5.79 (dd,J = 10.8 Hz, 2 Hz, 1H), 5.50-5.46 (m, 1H), 4.68-4.63 (m, 3H), 4.21-4.17(m, 2H), 3.80- 3.78 (m, 2H), 3.42-3.31 (m, 6H), 3.09-3.05 (m, 1H),1.61-1.60 (m, 4H), 1.48 (d, J = 6.8 Hz, 3H). 659.3 94.4 (3S,10R)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4-difluorophenyl)-3- ((methoxymethoxy) methyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1371

¹H NMR (400 MHz, CDCl₃) δ: 8.10 (s, 1H), 7.55-7.45 (m, 1H), 7.05 (t, J =8.0 Hz, 2H), 6.63 (dd, J = 16.8 Hz, 10.4 Hz, 1H), 6.41 (dd, J = 16.8 Hz,2.0 Hz, 1H), 5.78 (dd, J = 10.4 Hz, 2.0 Hz, 1H), 5.50-5.45 (m, 1H),4.70-4.61 (m, 2H), 4.29-4.11 (m, 2H), 3.70- 3.61 (m, 2H), 3.40 (s, 3H),3.38-3.30 (m, 3H), 3.07 (dd, J = 13.5, 2.7 Hz, 1H), 1.63 (d, J = 7.2 Hz,3H), 1.48 (d, J = 7.2 Hz, 3H). 595.2 60.6 (S)-7-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(2,6- difluorophenyl)-3-(methoxymethyl)- 9-(trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1372

¹H NMR (400 MHz, CDCl₃) δ: 8.04 (s, 1H), 7.35-7.24 (m, 2H), 7.13- 7.10(m, 1H), 6.62 (dd, J = 10.4 Hz, J = 16.4 Hz, 1H), 6.40 (dd, J = 2.0 Hz,J = 16.8 Hz, 1H), 5.77 (dd, J = 1.6 Hz, J = 10.4 Hz, 1H), 5.37-5.34 (m,1H), 4.85- 4.45 (m, 2H), 4.19-4.15 (m, 2H), 3.44 (d, J = 12.0 Hz, 1H),3.38-3.29 (m, 2H), 2.96 (d, J = 13.2 Hz, 1H), 2.80-2.50 (m, 10H), 1.59(dd, J = 3.2 Hz, J = 6.8 Hz, 4H), 1.49 (q, J = 3.6 Hz, 3H), 0.50-0.37(m, 4H). 705.2 77.2 (S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(3-chloro- 4-fluorophenyl)-3- ((4- cyclopropylpiperazin-1-yl)methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1373

¹H NMR (400 MHz, CDCl₃) δ: 8.07 (s, 1H), 7.30-7.25 (m, 2H), 7.14- 7.09(m, 1H), 6.62 (dd, J = 10.8 Hz, J = 16.8 Hz, 1H), 6.40 (dd, J = 1.6 Hz,J = 16.4 Hz, 1H), 5.77 (dd, J = 1.6 Hz, J = 10.4 Hz, 1H), 5.38-5.30 (m,1H), 4.76- 4.56 (m, 2H), 4.19-4.14 (m, 2H), 3.43-3.35 (m, 3H), 3.25-2.99(m, 9H), 2.89- 2.72 (m, 3H), 1.59 (dd, J = 3.2 Hz, J = 6.8 Hz, 4H), 1.49(q, J = 3.6 Hz, 3H), 1.44 (t, J = 7.2 Hz, 3H). 693.3 66.2(S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(3-chloro-4-fluorophenyl)-3- ((4ethylpiperazin- 1-yl)methyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1374

¹H NMR (400 MHz, CDCl₃) δ: 8.09 (s, 1H), 6.82 (t, J = 7.2 Hz, 2H), 6.62(dd, J = 10.8 Hz, J = 16.8 Hz, 1H), 6.40 (dd, J = 1.6 Hz, J = 16.4 Hz,1H), 5.77 (dd, J = 1.6 Hz, J = 10.4 Hz, 1H), 5.50-5.45 (m, 1H),4.85-4.52 (m, 2H), 4.22-4.16 (m, 2H), 3.67- 3.60 (m, 2H), 3.40 (s, 3H),3.37-3.30 (m, 3H), 3.07 (dd, J = 2.8 Hz, J = 13.2 Hz, 1H), 1.62 (d, J =6.8 Hz, 3H), 1.47 (d, J = 7.2 Hz, 3H). 613.2 88.5 (S)-7-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin- 1-yl)-3- (methoxymethyl)-9-(trifluoromethyl)- 10-(2,4,6- trifluorophenyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1375

¹H NMR (400 MHz, CDCl₃) δ: 8.07 (s, 1H), 7.29-7.25 (m, 1H), 7.08 (t, J =8.8 Hz, 1H), 6.66-6.59 (m, 1H), 6.43-6.39 (m, 1H), 5.78 (dd, J = 10.4Hz, 2.0 Hz, 1H), 5.38-5.35 (m, 1H), 4.71-4.59 (m, 2H), 4.20- 4.16 (m,2H), 3.50-3.30 (m, 3H), 3.04-3.00 (m, 1H), 2.85-2.83 (m, 1H), 2.43- 2.37(m, 7H), 1.60 (d, J = 7.2 Hz, 3H), 1.49 (d, J = 7.2 Hz, 3H). 642.3 93.9(3S,10R)-7- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-chloro- 2,4- difluorophenyl)-3- ((dimethylamino) methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1376

¹H NMR (400 MHz, CDCl₃) δ: 8.07 (s, 1H), 7.29-7.25 (m, 1H), 7.07 (t, J =8.8 Hz, 1H), 6.66-6.59 (m, 1H), 6.43-6.39 (m, 1H), 5.78 (dd, J = 10.0Hz, 2.0 Hz, 1H), 5.40-5.38 (m, 1H), 4.69-4.58 (m, 2H), 4.20- 4.17 (m,2H), 3.51-3.30 (m, 3H), 3.02-2.78 (m, 2H), 2.37-2.23 (m, 7H), 1.61 (d, J= 7.2 Hz, 3H), 1.48 (d, J = 7.2 Hz, 3H). 642.3 83.9 (3S,10S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(5-chloro- 2,4-difluorophenyl)-3- ((dimethylamino) methyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1377

¹H NMR (400 MHz, CDCl₃) δ: 7.83 (s, 1H), 7.52-7.46 (m, 1H), 7.05 (d, J =8.0 Hz, 1H), 6.63-6.56 (m, 1H), 6.39-6.34 (m, 1H), 5.78 (dd, J = 10.4Hz, 1.6 Hz, 1H), 5.47-5.44 (m, 1H), 3.98-3.90 (m, 3H), 3.82- 3.79 (m,5H), 3.70-3.62 (m, 2H), 3.40 (m, 3H), 3.36 (dd, J = 13.6 Hz, 2.8 Hz,1H), 3.06 (dd, J = 13.2 Hz, 2.8 Hz, 1H). 567.2 95.5 (S)-7-(4-acryloylpiperazin- 1-yl)-10-(2,6- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1378

¹H NMR (400 MHz, CDCl₃) δ: 7.80 (s, 1H), 7.23-7.15 (m, 4H), 6.63- 6.56(m, 1H), 6.39-6.34 (m, 1H), 5.78 (dd, J = 10.4 Hz, 2.0 Hz, 1H),5.36-5.32 (m, 1H), 3.93-3.80 (m, 8H), 3.40-3.37 (m, 1H), 2.97- 2.93 (m,1H), 2.84-2.79 (m, 3H), 2.60-2.45 (m, 9H), 1.31-1.09 (t, J = 8 Hz, 3H).631.3 78.9 (S)-7-(4- acryloylpiperazin- 1-yl)-3-((4- ethylpiperazin-1-yl)methyl)-10-(4- fluorophenyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1379

¹H NMR (400 MHz, CDCl₃) δ: 7.82 (s, 1H), 6.83 (t, J = 8.4 Hz, 2H), 6.59(dd, J = 16.8 Hz, 10.4 Hz, 1H), 6.37 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.79(dd, J = 10.8 Hz, 2 Hz, 1H), 5.48- 5.44 (m, 1H), 3.97-3.95 (m, 3H),3.81-3.79 (m, 5H), 3.69-3.63 (m, 2H), 3.44- 3.35 (m, 4H), 3.07 (dd, J =13.6 Hz, 2.8 Hz, 1H). 585.3 96.7 (S)-7-(4- acryloylpiperazin- 1-yl)-3-(methoxymethyl)- 9-(trifluoromethyl)- 10-(2,4,6- trifluorophenyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1380

¹H NMR (400 MHz, CDCl₃) δ: 7.81 (s, 1H), 7.35-7.24 (m, 2H), 7.15- 7.08(m, 1H), 6.67-6.51 (m, 1H), 6.38 (t, J = 14.0 Hz, 1H), 5.80-5.76 (m,1H), 5.40-5.32 (m, 1H), 5.06- 5.00 (m, 0.5H), 4.86-4.65 (m, 1H),4.44-4.28 (m, 1.5H), 4.05-3.99 (m, 0.5H), 3.76-3.67 (m, 2H), 3.40- 3.29(m, 1.5H), 2.99-2.96 (m, 1H), 2.82-2.77 (m, 3H), 2.71-2.42 (m, 9H),1.47- 1.36 (m, 6H), 1.09 (t, J = 6.8 Hz, 3H). 693.3 88.4(S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin- 1-yl)-10-(3-chloro-4-fluorophenyl)-3- ((4-ethylpiperazin- 1-yl)methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1381

695.4 19.1 (3S,10R)-7- ((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-3-((4- ethylpiperazin-1- yl)methyl)-10-(1- methyl-1H-indazol-7-yl)-9- (trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1382

695.4 49.1 (3S,10S)-7- ((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-3-((4- ethylpiperazin-1- yl)methyl)-10-(1- methyl-1H-indazol-7-yl)-9- (trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1383

¹H NMR (400 MHz, MeOH-d₄) δ 7.85 (d, J = 3.2 Hz, 1H), 7.35-7.19 (m, 4H),6.84 (ddd, J = 17.3, 10.7, 7.0 Hz, 1H), 6.21 (d, J = 16.7, 1H), 5.77 (d,J = 10.7 Hz, 1H), 5.36-5.26 (m, 1H), 4.89-4.76 (m, 1H), 4.57- 4.36 (m,3H), 4.25-4.16 (m, 1H), 4.13-3.89 (m, 4H), 3.81-3.69 (m, 2H), 3.65- 3.53(m, 2H), 3.40 (s, 3H), 3.39-3.24 (m, 4H), 3.09 (dd, J = 13.7, 2.8 Hz,1H). 591.2 66 (3S)-7-(7-acryloyl- 3-oxa-7,9- diazabicyclo[3.3.1]nonan-9-yl)-10-(4- fluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1384

¹H NMR (400 MHz, MeOH-d₄) δ 7.85 (d, J = 3.2 Hz, 1H), 7.34-7.17 (m, 4H),6.84 (ddd, J = 17.4, 10.7, 7.1 Hz, 1H), 6.21 (d, J = 16.8, 1H), 5.77 (d,J = 10.7 Hz, 1H), 5.37-5.27 (m, 1H), 4.89-4.75 (m, 1H), 4.57-4.36 (m,3H), 4.26- 4.15 (m, 1H), 4.14-3.89 (m, 4H), 3.81-3.69 (m, 2H), 3.67-3.52(m, 2H), 3.40 (s, 3H), 3.38-3.24 (m, 2H), 3.09 (dd, J = 13.7, 2.9 Hz,1H). 591.2 77.8 (3S)-7-(9-acryloyl- 3-oxa-7,9- diazabicyclo[3.3.1]nonan-7-yl)-10-(4- fluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1385

¹H NMR (400 MHz, CDCl₃) δ: 8.13 (s, 1H), 8.06 (s, 1H), 7.87 (dd, J = 0.8Hz, 8.0 Hz, 1H), 7.28-7.24 (m, 1H), 7.15 (d, J = 6.8 Hz, 1H), 6.66-6.59(m, 1H), 6.43-6.39 (m, 1H), 5.78 (dd, J = 2.0 Hz, 10.4 Hz, 1H),5.21-5.18 (m, 1H), 4.77- 4.60 (m, 2H), 4.39 (s, 1H), 4.22 (d, J = 13.6H, 2H), 3.95-3.92 (m, 1H), 3.65- 3.63 (m, 1H), 3.58 (s, 3H), 3.45-3.38(m, 4H), 3.02- 2.98 (m, 3H), 2.93-2.86 (m, 1H), 2.75-2.71 (m, 1H),1.75-1.71 (m, 2H), 1.64 (d, J = 7.2 Hz, 3H), 1.48 (d, J = 7.2 Hz, 3H).680.4 92.5 (3S)-3-(((1S,4S)-2- oxa-5- azabicyclo[2.2.1]heptan-5-yl)methyl)- 7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(1-methyl- 1H-indazol-7-yl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1386

¹H NMR (400 MHz, CDCl₃) δ: 8.05 (s, 1H), 7.30-7.27 (m, 1H), 7.26- 7.23(m, 1H), 7.13-7.08 (m, 1H), 6.65-6.59 (m, 1H), 6.42 (dd, J = 2.0 Hz,16.8 Hz, 1H), 5.78 (dd, J = 1.6 Hz, 10.0 Hz, 1H), 4.76-4.58 (m, 4H),4.17-4.11 (m, 2H), 3.72-3.69 (m, 4H), 3.38- 3.10 (m, 5H), 2.72-2.60 (m,4H), 1.57-1.50 (m, 6H). 666.3 71.6 (S)-8-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-11-(3-chloro- 4-fluorophenyl)-3- morpholino-10-(trifluoromethyl)- 3,4-dihydro- 2H,6H- [1,4]thiazepino[2,3-4-ij]quinazolin-6- one 1387

¹H NMR (400 MHz, CDCl3) δ: 7.81 (s, 1H), 7.32-7.23 (m, 2H), 7.15- 7.09(m, 1H), 6.66-6.50 (m, 1H), 6.37 (t, J = 14.8 Hz, 1H), 5.77 (t, J = 8.4Hz, 1H), 5.41-5.29 (m, 1H), 5.05-4.63 (m, 1.5H), 4.41- 4.25 (m, 1H),4.04-3.97 (m, 0.5H), 3.79-3.66 (m, 2H), 3.42-3.37 (m, 1H), 2.76 (d, J =18.4 Hz, 1H), 2.60-2.51 (m, 11H), 1.46-1.36 (m, 7H), 0.45-0.39 (m, 4H).705.3 71 (S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-10-(3-chloro- 4-fluorophenyl)-3- ((4- cyclopropylpiperazin-1-yl)methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1388

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.94- 7.86 (m, 2H), 7.26-7.24(m, 1H), 7.14-7.12 (m, 1H), 6.65-6.54 (m, 1H), 6.41- 6.34 (m, 1H),5.80-5.76 (m, 1H), 5.35-5.32 (m, 1H), 5.09-5.08 (m, 0.5H), 4.80- 4.68(m, 1H), 4.49-4.35 (m, 1.5H), 4.17-4.13 (m, 0.5H), 3.72-3.57 (m, 5H),3.39- 3.22 (m, 1.5H), 3.02-2.98 (m, 1H), 2.71-2.45 (m, 10H), 1.53-1.46(m, 4H), 1.39-1.25 (m, 3H), 0.42- 0.38 (m, 4H). 707.4 95.3 (3S,10S)-7-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin- 1-yl)-3-((4-cyclopropylpiperazin- 1-yl)methyl)-10- (1-methyl-1H- indazol-7-yl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1389

¹H NMR (400 MHz, CDCl₃) δ: 8.17 (s, 1H), 8.08 (s, 1H), 7.90 (d, J = 8.8Hz, 1H), 7.26-7.24 (m, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.67-6.60 (m, 1H),6.44-6.39 (m, 1H), 5.81 (d, J = 12.4 Hz, 1H), 5.47 (s, 1H), 4.27 (d, J =13.6 Hz, 2H), 3.57-3.39 (m, 5H), 3.22-3.07 (m, 5H), 3.01- 3.96 (m, 11H),1.66 (d, J = 6.8 Hz, 3H), 1.49 (d, J = 6.8 Hz, 3H), 1.36 (t, J = 7.2 Hz,3H). 695.4 69.1 (3S,10S)-7- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-3-((4- ethylpiperazin-1- yl)methyl)-10-(1- methyl-1H-indazol-7-yl)-9- (trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1390

¹H NMR (400 MHz, CDCl₃) δ: 7.80 (s, 1H), 7.21-7.15 (m, 1H), 7.05- 6.90(m, 2H), 6.63-6.50 (m, 1H), 6.40-6.30 (dd, J = 2 Hz, 16.8 Hz, 1H),5.80-5.75 (m, 1H), 5.36-5.30 (m, 1H), 3.95-3.93 (m, 3H), 3.80- 3.75 (m,5H), 3.50-3.40 (m, 1H), 3.03-2.90 (m, 1H), 2.85-2.45 (m, 11H), 0.44-0.39 (m, 4H). 661.3 96.7 (3S,10R)-7-(4- acryloylpiperazin- 1-yl)-3-((4-cyclopropylpiperazin- 1-yl)methyl)-10- (2,4- difluorophenyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1391

¹H NMR (400 MHz, CDCl₃) δ: 7.80 (s, 1H), 7.21-7.15 (m, 1H), 7.06- 6.90(m, 2H), 6.63-6.50 (m, 1H), 6.40-6.30 (m, 1H), 5.80-5.75 (m, 1H), 5.41-5.35 (m, 1H), 3.94-3.92 (s, 3H), 3.83-3.75 (m, 5H), 3.48-3.40 (m, 1H),3.02- 2.90 (m, 1H), 2.81-2.45 (m, 11H), 0.44-0.39 (m, 4H). 661.3 95.9(3S,10S)-7-(4- acryloylpiperazin- 1-yl)-3-((4- cyclopropylpiperazin-1-yl)methyl)-10- (2,4- difluorophenyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1392a

¹H NMR (400 MHz, MeOH-d₄) δ 8.16 (s, 1H), 8.06 (s, 1H), 7.16 (dd, J =8.0, 4.8 Hz, 1H), 6.97 (dd, J = 9.7, 7.9 Hz, 1H), 6.82 (dd, J = 16.8,10.6 Hz, 1H), 6.28 (dd, J = 16.8, 1.9 Hz, 1H), 5.81 (dd, J = 10.6, 1.9Hz, 1H), 5.35 (ddt, J = 8.3, 5.3, 3.1 Hz, 1H), 4.16-4.04 (m, 2H),4.00-3.74 (m, 6H), 3.73-3.60 (m, 2H), 3.57 (s, 3H), 3.36 (s, 3H),3.35-3.33 (m, 1H), 3.13 (dd, J = 13.7, 3.0 Hz, 1H). 603.2 97.2(3S,10S)-7-(4- acryloylpiperazin- 1-yl)-10-(4-fluoro- 1-methyl-1H-indazol-7-yl)-3- (methoxymethyl)- 9-(trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1392

¹H NMR (400 MHz, MeOH-d₄) δ 8.15 (s, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.38(t, J = 9.1 Hz, 1H), 5.42- 5.34 (m, 1H), 4.83-4.56 (br s, 2H), 4.41-4.21(m, 2H), 3.73-3.40 (m, 5H), 3.39 (s, 3H), 3.17 (dd, J = 13.6, 3.0 Hz,1H), 1.56 (d, J = 6.9 Hz, 3H), 1.42 (d, J = 6.9 Hz, 3H). 632.2 64.9(3S,10S)-7- ((3S,5R)-4- (acryloyl-d3)-3,5- dimethylpiperazin-1-yl)-10-(5-chloro- 2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1393

¹H NMR (400 MHz, MeOH-d₄) δ 8.15 (s, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.37(t, J = 9.1 Hz, 1H), 5.41- 5.31 (m, 1H), 4.83-4.54 (br s, 2H), 4.39-4.29(m, 2H), 3.74 (t, J = 9.2 Hz, 1H), 3.62 (dd, J = 9.2, 4.8 Hz, 1H), 3.49(dd, J = 13.5, 4.7 Hz, 1H), 3.45-3.37 (m, 2H), 3.40 (s, 3H), 3.15 (dd, J= 13.7, 3.0 Hz, 1H), 1.57 (d, J = 7.0 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H).632.2 95.4 (3S,10R)-7- ((3S,5R)-4- (acryloyl-d3)-3,5- dimethylpiperazin-1-yl)-10-(5-chloro- 2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1394

¹H NMR (400 MHz, CDCl₃) δ: 7.74 (s, 1H), 7.29-7.25 (m, 1H), 7.07 (t, J =8.4 Hz, 1H), 6.58-6.45 (m, 2H), 5.82 (d, J = 10 Hz, 1H), 5.44-5.38 (m,1H), 5.03-4.61 (m, 2H), 4.44- 4.42 (m, 1H), 4.23-3.64 (m, 4H), 3.54-3.25(m, 5H), 3.05 (d, J = 13.6 Hz, 1H), 2.22-1.66 (m, 4H). 627.2 93.5(3S,10R)-7- ((1R,5S)-8- acryloyl-3,8- diazabicyclo[3.2.1]octan-3-yl)-10-(5- chloro-2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1395

¹H NMR (400 MHz, CDCl₃) δ: 7.76-7.32 (m, 1H), 7.29-7.25 (m, 1H), 7.07(t, J = 8.4 Hz, 1H), 6.58-6.45 (m, 2H), 5.82 (d, J = 10 Hz, 1H),5.45-5.41 (m, 1H), 5.05-4.57 (m, 2H), 4.44-4.42 (m, 1H), 4.21- 3.62 (m,4H), 3.54-3.24 (m, 5H), 3.05 (d, J = 15.6 Hz, 1H), 2.27-1.64 (m, 4H).627.2 17.3 (3S,10S)-7- ((1R,5S)-8- acryloyl-3,8- diazabicyclo[3.2.1]octan-3-yl)-10-(5- chloro-2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1396

¹H NMR (400 MHz, CDCl₃) δ: 7.82 (s, 1H), 7.25-7.23 (m, 1H), 7.05 (t, J =8.8 Hz, 1H), 6.62-6.55 (m, 1H), 6.39 (dd, J = 16.4 Hz, 1.6 Hz, 1H), 5.80(dd, J = 10.8 Hz, 2.0 Hz, 1H), 5.14- 4.70 (m, 4H), 4.37-4.34 (m, 2H),3.87-3.75 (m, 8H), 3.48-3.39 (m, 2H). 613.2 95.1 (R)-8′-(4-acryloylpiperazin- 1-yl)-11′-(5-chloro- 2,4- difluorophenyl)- 10′-(trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3-4-ij]quinazolin-6′- one 1397

¹H NMR (400 MHz, CDCl₃) δ: 7.82 (s, 1H), 7.25-7.23 (m, 1H), 7.05 (t, J =8.8 Hz, 1H), 6.62-6.55 (m, 1H), 6.39 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.80(dd, J = 10.4 Hz, 2.0 Hz, 1H), 5.16- 4.70 (m, 4H), 4.37-4.34 (m, 2H),3.94-3.81 (m, 8H), 3.48-3.40 (m, 2H). 613.2 78.2 (S)-8′-(4-acryloylpiperazin- 1-yl)-11′-(5-chloro- 2,4- difluorophenyl)- 10′-(trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]-6′- one 1398

¹H NMR (400 MHz, CDCl₃) δ: 8.10 (s, 1H), 7.24-7.15 (m, 4H), 6.66- 6.59(m, 1H), 6.43-6.39 (m, 1H), 5.78 (dd, J = 10.4 Hz, 2.0 Hz, 1H),4.77-4.64 (m, 3H), 4.30-4.13 (m, 3H), 3.49-3.37 (m, 3H), 2.95- 2.84 (m,2H), 2.52-2.26 (m, 3H), 0.89-0.85 (m, 6H). 577.2 44.2 (R)-8-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin- 1-yl)-11-(4- fluorophenyl)-3-(hydroxymethyl)- 10- (trifluoromethyl)- 3,4-dihydro- 2H,6H-[1,4]thiazepino[2,3, 4-ij]quinazolin-6- one 1399

¹H NMR (400 MHz, CDCl₃) δ: 8.10 (s, 1H), 7.24-7.15 (m, 4H), 6.66- 6.59(m, 1H), 6.43-6.39 (m, 1H), 5.78 (dd, J = 10.4 Hz, 2.0 Hz, 1H),4.78-4.77 (m, 3H), 4.21-4.13 (m, 3H), 3.69-3.67 (m, 1H), 3.47- 3.35 (m,3H), 2.91-2.89 (m, 2H), 2.51-2.38 (m, 2H), 0.89-0.83 (m, 6H). 577.2 95.5(S)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-11-(4-fluorophenyl)-3- (hydroxymethyl)- 10- (trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3, 4-ij]quinazolin-6- one 1400

¹H NMR (400 MHz, CDCl₃) δ: 7.47 (s, 1H), 7.32-7.28 (m, 1H), 7.11- 7.06(m, 1H), 6.57-6.42 (m, 2H), 5.79 (dd, J = 10.0 Hz, 2.4 Hz, 1H),5.43-5.31 (m, 1H), 4.85-4.79 (m, 1.5H), 4.50-4.41 (m, 2H), 4.15- 4.12(m, 0.5H), 3.83-3.80 (m, 0.5H), 3.64-3.61 (m, 0.5H), 3.47-3.30 (m, 2H),3.07-3.02 (m, 1H), 2.77- 2.39 (m, 12H), 2.22-2.14 (m, 1H), 2.05-1.92 (m,3H), 1.09-1.05 (m, 3H). 675.62 43.7 (3S)-7-((1R,5S)-8- acryloyl-3,8-diazabicyclo[3.2.1] octan-3-yl)-9- chloro-10-(5- chloro-2,4-difluorophenyl)-3- ((4-ethylpiperazin- 1-yl)methyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1401

¹H NMR (400 MHz, CDCl₃) δ: 7.77 (s, 1H), 7.24-7.22 (m, 1H), 7.05 (t, J =8.8 Hz, 1H), 6.57-6.43 (m, 2H), 5.81 (dd, J = 10.0 Hz, 2.4 Hz, 1H),5.05-4.80 (m, 5H), 4.43-4.35 (m, 4H), 4.16-3.71 (m, 2H), 3.47- 3.39 (m,3H), 2.06-1.83 (m, 4H). 639.2 76.6 (R)-8′-((1R,5S)-8- acryloyl-3,8-diazabicyclo[3.2.1] octan-3-yl)-11′-(5- chloro-2,4- difluorophenyl)-10′- (trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′-[1,4]thiazepino[2,3, 4-ij]quinazolin]-6′- one 1402

¹H NMR (400 MHz, CDCl₃) δ: 7.77 (s, 1H), 7.24-7.22 (m, 1H), 7.05 (t, J =8.4 Hz, 1H), 6.57-6.43 (m, 2H), 5.81 (dd, J = 9.6 Hz, 2.4 Hz, 1H),5.08-4.71 (m, 5H), 4.48-4.35 (m, 4H), 4.19-3.70 (m, 2H), 3.47- 3.35 (m,3H), 2.14-1.78 (m, 4H). 639.2 6.8 (S)-8′-((1R,5S)-8- acryloyl-3,8-diazabicyclo[3.2.1] octan-3-yl)-11′-(5- chloro-2,4- difluorophenyl)-10′- (trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′-[1,4]thiazepino[2,3, 4-ij]quinazolin-6′- one 1403

¹H NMR (400 MHz, CDCl₃) δ: 7.74 (s, 1H), 7.09-7.05 (m, 1H), 6.60- 6.45(m, 2H), 5.80 (d, J = 11.6 Hz, 1H), 5.46-5.30 (m, 1H), 4.90-4.86 (m,1.5H), 4.43 (m, 2H), 4.09-3.88 (m, 1H), 3.66-3.51 (m, 1H), 3.40-3.32 (m,1.5H), 3.04 (d, J = 15.2 Hz, 1H), 2.92- 2.05 (m, 13H), 1.98-1.82 (m,4H), 1.16 (m, 3H). 709.3 80.3 (3S)-7-((1R,5S)-8- acryloyl-3,8-diazabicyclo[3.2.1] octan-3-yl)-10-(5- chloro-2,4- difluorophenyl)-3-((4-ethylpiperazin- 1-yl)methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1404

¹H NMR (400 MHz, MeOH-d₄) δ 8.14 (s, 1H), 7.30 (q, J = 8.0 Hz, 1H), 7.14(t, J = 9.1 Hz, 2H), 5.42-5.33 (m, 1H), 4.81- 4.52 (m, 2H), 4.40-4.20(m, 2H), 3.70 (t, J = 9.1 Hz, 1H), 3.59 (dd, J = 9.2, 4.9 Hz, 1H), 3.51(dd, J = 13.5, 4.7 Hz, 1H), 3.45-3.40 (m, 1H), 3.39 (s, 3H), 3.38-3.33(m, 1H), 3.15 (dd, J = 13.6, 2.9 Hz, 1H), 1.57 (d, J = 7.0 Hz, 3H), 1.42(d, J = 6.9 Hz, 3H). 598.2 80.9 (3S,10S)-7- ((3S,5R)-4-(acryloyl-d3)-3,5- dimethylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-3-(methoxymethyl)- 9-(trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1405

¹H NMR (400 MHz, MeOH-d₄) δ 8.15 (s, 1H), 7.33 (q, J = 7.4 Hz, 1H), 7.14(t, J = 7.5 Hz, 2H), 5.41-5.29 (m, 1H), 4.82- 4.53 (br s, 2H), 4.39-4.19(m, 2H), 3.72 (t, J = 9.2 Hz, 1H), 3.61 (dd, J = 9.2, 4.8 Hz, 1H), 3.48(dd, J = 13.5, 4.7 Hz, 1H), 3.44-3.33 (m, 2H), 3.39 (s, 3H), 3.14 (dd, J= 13.6, 2.9 Hz, 1H), 1.58 (d, J = 6.9 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H).598.2 88.6 (3S,10R)-7- ((3S,5R)-4- (acryloyl-d3)-3,5- dimethylpiperazin-1-yl)-10-(2,4- difluorophenyl)-3- (methoxymethyl)- 9-(trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1406

¹H NMR (400 MHz, MeOH-d₄) δ 8.22 (s, 1H), 8.16 (s, 1H), 7.18 (dd, J =8.0, 4.8 Hz, 1H), 6.97 (dd, J = 9.7, 8.0 Hz, 1H), 6.85 (dd, J = 16.7,10.5 Hz, 1H), 6.30 (dd, J = 16.6, 2.0 Hz, 1H), 5.81 (dd, J = 10.6, 2.0Hz, 1H), 5.39-5.31 (m, 1H), 4.84-4.46 (m, 3H), 4.39 (d, J = 13.8 Hz,1H), 4.30 (d, J = 13.6 Hz, 1H), 3.73-3.60 (m, 2H), 3.56 (s, 3H), 3.55-3.38 (m, 3H), 3.36 (s, 2H), 3.35-3.33 (m, 1H), 3.15 (dd, J = 13.7, 3.0Hz, 1H), 1.60 (d, J = 7.0 Hz, 3H), 1.47-1.39 (m, 3H). 631.2 75.9(3S,10R)-7- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(6-fluoro- 1-methyl-1H- indazol-7-yl)-3- (methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1407

¹H NMR (400 MHz, CDCl₃) δ: 8.06 (s, 1H), 7.23-7.15 (m, 4H), 6.63 (dd, J= 2.0 Hz, J = 16.4 Hz, 1H), 6.41 (dd, J = 1.6 Hz, J = 14.4 Hz, 1H), 5.77(dd, J = 2.0 Hz, J = 10.4 Hz, 1H), 4.67-4.62 (m, 4H), 4.16 (d, J = 13.2Hz, 2H), 3.52-3.46 (m, 1H), 3.35-3.31 (m, 6H), 3.26- 3.18 (m, 1H), 3.02(dd, J = 4.4 Hz, J = 14.8 Hz, 1H), 2.76-2.58 (m, 1H), 1.57- 1.53 (m,6H). 591.2 92.7 (R)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(4- fluorophenyl)-3- (methoxymethyl)- 10- (trifluoromethyl)-3,4-dihydro- 2H,6H- [1,4]thiazepino[2,3, 4-ij]quinazolin-6- one 1408

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.23-7.15 (m, 4H), 6.62 (dd, J =10.4 Hz, J = 16.8 Hz, 1H), 6.41 (dd, J = 1.6 Hz, J = 16.4 Hz, 1H), 5.77(dd, J = 2.0 Hz, J = 10.4 Hz, 1H), 4.73-4.52 (m, 4H), 4.16 (d, J = 12.8Hz, 2H), 3.56-3.44 (m, 1H), 3.35-3.26 (m, 6H), 3.23- 3.19 (m, 1H), 3.02(dd, J = 4.8 Hz, J = 15.2 Hz, 1H), 2.77-2.53 (m, 1H), 1.59- 1.52 (m,6H). 591.2 83.7 (S)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(4- fluorophenyl)-3- (methoxymethyl)- 10- (trifluoromethyl)-3,4-dihydro- 2H,6H- [1,4]thiazepino[2,3, 4-ij]quinazolin-6- one 1409

¹H NMR (400 MHz, CDCl₃) δ 8.04 (s, 1H), 7.22-7.14 (m, 3H), 6.66- 6.59(m, 1H), 6.43 (dd, J = 1.6 Hz, 16.8 Hz, 1H), 5.78 (dd, J = 1.6 Hz, 10.4Hz, 1H), 4.94-4.91 (m, 1H), 4.74-4.57 (m, 2H), 4.23- 4.07 (m, 3H),3.62-3.60 (m, 1H), 3.41-3.29 (m, 12H), 3.14-3.06 (m, 1H), 2.82- 2.79 (m,1H), 1.66 (d, J = 5.2 Hz, 3H), 1.44 (d, J = 4.4 Hz, 3H). 635.3 96.58-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-11-(4-fluorophenyl)-3,3- bis(methoxymethyl)- 10- (trifluoromethyl)-3,4-dihydro- 2H,6H- [1,4]thiazepino[2,3, 4-ij]quinazolin-6- one 1410

¹H NMR (400 MHz, CDCl₃) δ: 8.05 (s, 1H), 7.32-7.26 (m, 1H), 7.07- 7.02(m, 1H), 6.66-6.59 (m, 1H), 6.43 (dd, J = 1.6 Hz, 16.8 Hz, 1H), 5.78(dd, J = 1.2 Hz, 10.0 Hz, 1H), 4.95- 4.92 (m, 1H), 4.77-4.54 (m, 2H),4.22-4.06 (m, 3H), 3.62-3.57 (m, 1H), 3.38- 3.34 (m, 11H), 3.21-3.11 (m,1H), 2.90-2.86 (m, 1H), 1.64-1.63 (m, 3H), 1.44- 1.43 (m, 3H). 687.395.3 8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-11-(5-chloro-2,4- difluorophenyl)- 3,3- bis(methoxymethyl)- 10- (trifluoromethyl)-3,4-dihydro- 2H,6H- [1,4]thiazepino[2,3, 4-ij]quinazolin-6- one 1411

¹H NMR (400 MHz, CDCl₃) δ: 8.12 (s, 1H), 8.05 (s, 1H), 7.89 (d, J = 7.6Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 5.6 Hz, 1H), 6.67-6.59(m, 1H), 6.41 (d, J = 16.4 Hz, 1H), 5.77 (d, J = 12 Hz, 1H), 5.40-5.36(m, 1H), 4.77-4.59 (m, 2H), 4.20 (t, J = 12.4 Hz, 2H), 3.55 (s, 3H),3.40-3.35 (m, 3H), 2.96 (d, J = 14.4 Hz, 1H), 2.82-2.50 (m, 10H), 1.59(m, 3H), 1.53-1.51 (m, 3H), 1.25 (s, 1H), 0.43-0.42 (m, 4H). 707.4 0(3S,10R)-7- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-3-((4-cyclopropylpiperazin- 1-yl)methyl)-10- (1-methyl-1H- indazol-7-yl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1412

¹H NMR (400 MHz, CDCl₃) δ: 8.13 (s, 1H), 8.06 (s, 1H), 7.87 (d, J = 8Hz, 1H), 7.28-7.24 (m, 1H), 7.14 (d, J = 6.8 Hz, 1H), 6.67-6.60 (m, 1H),6.42 (d, J = 16.8 Hz, 1H), 5.77 (d, J = 10.8 Hz, 1H), 5.38-5.35 (m, 1H),4.86- 4.50 (m, 2H), 4.20 (t, J = 13.6 Hz, 2H), 3.57 (s, 3H), 3.43-3.33(m, 3H), 2.99 (d, J = 15.6 Hz, 1H), 2.73-2.44 (m, 10H), 1.64-1.62 (m,3H), 1.50-1.48 (m, 3H), 1.25 (s, 1H), 0.44-0.41 (m, 4H). 707.4 85.4(3S,10S)-7- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-3-((4-cyclopropylpiperazin- 1-yl)methyl)-10- (1-methyl-1H- indazol-7-yl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1413

¹H NMR (400 MHz, CDCl₃) δ: 8.06 (s, 1H), 7.23-7.15 (m, 4H), 6.62 (dd, J= 10.4 Hz, J = 16.4 Hz, 1H), 6.41 (dd, J = 1.6 Hz, J = 16.8 Hz, 1H),5.77 (dd, J = 2.0 Hz, J = 10.4 Hz, 1H), 5.43-5.41 (m, 1H), 4.82-4.54 (m,2H), 4.21- 4.16 (m, 2H), 3.69-3.62 (m, 2H), 3.39-3.29 (m, 3H), 2.98-2.94(m, 1H), 1.62 (d, J = 7.2 Hz, 3H), 1.47 (d, J = 7.2 Hz, 3H). 580.2 95.1(S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(4-fluorophenyl)-3- ((methoxy- d3)methyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1414

¹H NMR (400 MHz, CDCl₃) δ: 8.07 (s, 1H), 7.23-7.13 (m, 1H), 7.08- 6.92(m, 2H), 6.63 (dd, J = 16.8 Hz, 6.0 Hz, 1H), 6.41 (dd, J = 16.8 Hz, 1.6Hz, 1H), 5.78 (dd, J = 10.8 Hz, 1.6 Hz, 1H), 5.51-5.38 (m, 1H),5.00-4.40 (m, 2H), 4.25-4.14 (m, 2H), 3.74- 3.47 (m, 4H), 3.43-3.28 (m,3H), 3.07-2.97 (m, 1H), 1.63 (d, J = 7.2 Hz, 3H), 1.48 (d, J = 6.4 Hz,3H), 1.18 (t, J = 6.8 Hz, 3H). 609.2 91.8 (3S)-7-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-3-(ethoxymethyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1415

¹H NMR (400 MHz, CDCl₃) δ: 8.06 (s, 1H), 7.25-7.14 (m, 4H), 6.63 (dd, J= 16.4 Hz, 10.8 Hz, 1H), 6.41 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.78 (dd, J= 10.4 Hz, 2.0 Hz, 1H), 5.47-5.37 (m, 1H), 4.90-4.40 (m, 2H), 4.25-4.13(m, 2H), 3.75- 3.47 (m, 4H), 3.43-3.26 (m, 3H), 2.96 (dd, J = 13.6 Hz,2.8 Hz, 1H), 1.62 (d, J = 7.2 Hz, 3H), 1.47 (d, J = 6.8 Hz, 3H), 1.18(t, J = 6.8 Hz, 3H). 591.3 90.1 (S)-7-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-3- (ethoxymethyl)-10- (4-fluorophenyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1416

¹H NMR (400 MHz, MeOH-d₄) δ 8.16 (s, 1H), 8.06 (s, 1H), 7.16 (dd, J =8.0, 4.8 Hz, 1H), 6.97 (dd, J = 9.6, 7.9 Hz, 1H), 6.82 (dd, J = 16.8,10.6 Hz, 1H), 6.28 (dd, J = 16.8, 1.9 Hz, 1H), 5.81 (dd, J = 10.6, 1.9Hz, 1H), 5.38-5.29 (m, 1H), 4.16-4.04 (m, 2H), 4.00- 3.75 (m, 5H),3.73-3.59 (m, 3H), 3.56 (s, 3H), 3.35 (s, 3H), 3.35-3.23 (m, 1H), 3.13(dd, J = 13.6, 3.0 Hz, 1H). 603.1 71.3 (3S,10R)-7-(4- acryloylpiperazin-1-yl)-10-(6-fluoro- 1-methyl-1H- indazol-7-yl)-3- (methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1417

¹H NMR (400 MHz, CDCl₃) δ: 8.11 (s, 1H), 7.35-7.27 (m, 1H), 7.15- 7.09(m, 1H), 6.72-6.63 (m, 1H), 6.49-6.42 (m, 1H), 5.84-5.80 (m, 1H), 5.52-5.47 (m, 1H), 4.75-4.64 (m, 2H), 4.26-4.22 (m, 2H), 3.75-3.66 (m, 2H),3.45- 3.34 (m, 3H), 3.10-3.05 (m, 1H), 1.69-1.67 (m, 3H), 1.54-1.50 (m,3H). 632.3 92.5 (3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-chloro- 2,4- difluorophenyl)-3- ((methoxy- d3)methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1418

¹H NMR (400 MHz, CD₃OD) δ 8.08 (s, 1H), 7.21-7.15 (m, 1H), 7.00- 6.94(m, 2H), 6.65-5.58 (m, 1H), 6.44-6.38 (m, 1H), 5.80-5.76 (m, 1H), 5.48-5.45 (m, 1H), 4.74-4.57 (m, 2H), 4.19-4.17 (m, 2H), 3.65-3.58 (m, 2H),3.40- 3.34 (m, 3H), 3.06-2.98 (m, 1H), 1.63-1.60 (m, 3H), 1.47 (d, J =7.2 Hz, 3H). 598.3 95.4 (3S)-7-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-3- ((methoxy-d3)methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1419

¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.23- 7.16 (m, 4H), 6.66-6.59(m, 1H) 6.43-6.38 (m, 1H), 5.78-5.75 (m, 1H), 5.45- 5.42 (m, 1H),4.78-4.53 (m, 2H), 4.21-4.15 (m, 2H), 3.38-3.27 (m, 2H), 3.14- 3.10 (m,1H), 2.90-2.86 (m, 1H), 1.64 (d, J = 5.2 Hz, 3H), 1.48-1.45 (m, 6H).547.2 95.7 (S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(4- fluorophenyl)-3- methyl-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1420

¹H NMR (400 MHz, CDCl₃) δ: 8.05 (s, 1H), 7.32-7.26 (m, 1H), 7.05 (t, J =8.4 Hz, 1H), 6.66-6.59 (m, 1H), 6.43 (dd, J = 2.0 Hz, 16.8 Hz, 1H), 5.78(dd, J = 1.6 Hz, 10.4 Hz, 1H), 4.96- 4.59 (m, 3H), 4.21-4.06 (m, 3H),3.63-3.59 (m, 1H), 3.39-3.34 (m, 11H), 3.20- 3.10 (m, 1H), 2.92-2.85 (m,1H), 1.71-1.61 (m, 3H), 1.51-1.38 (m, 3H). 687.3 93 (S)-8-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin- 1yl)-11-(5-chloro- 2,4-difluorophenyl)- 3,3- bis(methoxymethyl)- 10- (trifluoromethyl)-3,4-dihydro- 2H,6H- [1,4]thiazepino[2,3, 4-ij]quinazolin-6- one 1421

¹H NMR (400 MHz, CDCl₃) δ: 8.10 (s, 1H), 7.37-7.34 (m, 1H), 7.10 (t, J =11.2 Hz, 1H), 6.72-6.63 (m, 1H), 6.48 (dd, J = 2.4 Hz, 22.0 Hz, 1H),5.84 (dd, J = 2.4 Hz, 14.0 Hz, 1H), 5.00-4.58 (m, 3H), 4.27- 4.11 (m,3H), 3.69-3.62 (m, 1H), 3.43-3.35 (m, 11H), 3.25-3.14 (m, 1H), 2.95-2.90 (m, 1H), 1.75-1.69 (m, 3H), 1.50-1.48 (m, 3H). 687.3 91(R)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-11-(5-chloro-2,4- difluorophenyl)- 3,3- bis(methoxymethyl)- 10- (trifluoromethyl)-3,4-dihydro- 2H,6H- [1,4]thiazepino[2,3, 4-ij]quinazolin-6- one 1422

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.26-7.24 (m, 1H), 7.04 (t, J =8.8 Hz, 1H), 6.66-6.59 (m, 1H), 6.40 (d, J = 16.0 Hz, 1H), 5.76 (d, J =20 Hz, 1H), 4.89-4.45 (m, 4H), 4.14-4.13 (m, 2H), 3.42-3.15 (m, 5H),2.86- 2.53 (m, 4H), 1.90-1.73 (m, 4H), 1.55-1.43 (m, 6H). 668.3 94.1(3S)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- (pyrrolidin-1-yl)- 10- (trifluoromethyl)-3,4-dihydro- 2H,6H- [1,4]thiazepino[2,3, 4-ij]quinazolin-6- one 1423

¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.22-7.17 (m, 1H), 7.06- 6.93(m, 2H), 6.64-6.59 (m, 1H), 6.44-6.38 (m, 1H), 5.78 (dd, J = 10.4 Hz,2.0 Hz, 1H), 5.48-5.45 (m, 1H), 4.66-4.63 (m, 2H), 4.23-4.19 (m, 2H),3.70- 3.60 (m, 2H), 3.40-3.30 (m, 3H), 3.04-2.99 (m, 1H), 1.63-1.61 (m,3H), 1.47 (d, J = 6.8 Hz, 3H). 598.2 95.1 (3S,10R)-7- ((3S,5R)-4-acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-3-((methoxy- d3)methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1424

¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.19-7.17 (m, 1H), 7.03- 6.94(m, 2H), 6.64-6.59 (m, 1H), 6.44-6.39 (m, 1H), 5.78 (dd, J = 12.4 Hz,2.0 Hz, 1H), 5.46-5.43 (m, 1H), 4.76-4.64 (m, 2H), 4.21-4.16 (m, 2H),3.67- 3.65 (m, 2H), 3.40-3.32 (m, 3H), 3.06-3.01 (m, 1H), 1.63-1.61 (m,3H), 1.52- 1.46 (m, 3H). 598.2 95.4 (3S,10S)-7- ((3S,5R)-4-acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-3-((methoxy- d3)methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1425

¹H NMR (400 MHz, MeOH-d₄) δ 10.28 (s, 1H), 8.01-7.94 (m, 1H), 7.49 (q, J= 8.4 Hz, 1H), 7.37 (td, J = 9.8, 3.1 Hz, 1H), 7.09 (td, J = 9.8, 2.7Hz, 1H), 6.90- 6.71 (m, 1H), 6.33-6.22 (m, 1H), 5.81 (q, J = 6.8 Hz,2H), 4.84-4.57 (m, 2H), 4.55-4.36 (m, 3H), 4.35- 4.17 (m, 1H), 3.95-3.68(m, 2H), 3.67-3.35 (m, 4H), 1.45-1.25 (m, 6H). 635.2 69.25-(8′-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin- 1-yl)-6′-oxo-10′-(trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]- 11′-yl)-2,4- difluorobenzaldehyde 1426

¹H NMR (400 MHz, MeOH-d₄) δ 7.97 (d, J = 2.5 Hz, 1H), 7.44 (q, J = 8.7Hz, 1H), 7.13 (td, J = 9.7, 3.0 Hz, 1H), 6.90-6.70 (m, 1H), 6.32-6.22(m, 1H), 5.85- 5.76 (m, 1H), 5.65 (s, 1H), 4.85-4.59 (m, 3H), 4.54- 4.15(m, 3H), 3.95-3.70 (m, 2H), 3.63-3.45 (m, 2H), 3.37 (s, 3H), 3.30 (s,3H), 1.48-1.27 (m, 6H). 681.2 76 8′-((2S,5R)-4- acryloyl-2,5-dimethylpiperazin- 1-yl)-11′-(5- (dimethoxymethyl)- 2,4-difluorophenyl)- 10′- (trifluoromethyl)- 2′H,4′H,6′H-spiro[oxetane-3,3′- [1,4]thiazepino[2,3, 4-ij]quinazolin]-6′- one 1427

¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 7.20- 7.16 (m, 1H), 7.08-6.95(m, 2H), 6.66-6.59 (m, 1H), 6.43-6.39 (m, 1H), 5.78 (d, J = 10.4 Hz,1H), 5.48-5.43 (m, 1H), 4.66-4.57 (m, 2H), 4.19 (t, J = 13.6 Hz, 2H),3.38-3.29 (m, 2H), 3.21- 3.15 (m, 1H), 2.92-2.89 (m, 1H), 1.64 (d, J =7.2 Hz, 3H), 1.48-1.46 (m, 6H). 565.2 95 (3S)-7-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-3-methyl-9- (trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1428

¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.21- 7.15 (m, 1H), 7.06-6.94(m, 2H), 6.66-6.59 (m, 1H), 6.40 (dd, J = 1.6 Hz, J = 16.4 Hz, 1H), 5.77(dd, J = 2.0 Hz, J = 10.8 Hz, 1H), 5.41-5.37 (m, 1H), 5.21- 5.04 (m,1H), 4.79-4.53 (m, 2H), 4.21-4.17 (m, 2H), 3.47-3.45 (m, 1H), 3.39- 3.30(m, 2H), 3.12-2.97 (m, 4H), 2.91-2.82 (m, 1H), 2.61-2.55 (m, 2H), 2.18-1.96 (m, 2H), 1.61 (m, 3H), 1.48 (d, J = 7.2 Hz, 3H). 652.3 72(3S,10S)-7- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(2,4-difluorophenyl)-3- (((S)-3- fluoropyrrolidin-1- yl)methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1429

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.21- 7.15 (m, 1H), 7.06-6.94(m, 2H), 6.66-6.59 (m, 1H), 6.50 (dd, J = 2.0 Hz, J = 16.8 Hz, 1H), 5.77(dd, J = 2.0 Hz, J = 10.4 Hz, 1H), 5.37-5.33 (m, 1H), 5.21- 5.04 (m,1H), 4.78-4.52 (m, 2H), 4.18 (d, J = 12.8 Hz, 2H), 3.48-3.44 (m, 1H),3.38-3.30 (m, 2H), 3.12- 2.95 (m, 4H), 2.88-2.83 (m, 1H), 2.60-2.58 (m,2H), 2.17-1.98 (m, 2H), 1.61 (m, 3H), 1.48 (d, J = 7.2 Hz, 3H). 652.3 79(3S,10R)-7- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(2,4-difluorophenyl)-3- (((S)-3- fluoropyrrolidin-1- yl)methyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1430

¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.26- 7.13 (m, 4H), 6.63 (dd, J= 10.8 Hz, 16.8 Hz, 1H), 6.45- 6.38 (m, 1H), 5.78 (d, J = 11.2 Hz, 1H),4.84-4.53 (m, 4H), 4.39-4.32 (m, 1H), 4.25-4.11 (m, 2H), 3.82- 3.74 (m,1H), 3.69-3.58 (m, 2H), 3.55-3.36 (m, 3H), 2.84 (brs, 1H), 2.75-2.69 (m,1H), 2.64-2.58 (m, 1H), 1.65 (d, J = 7.2 Hz, 3H), 1.47 (d, J = 6.8 Hz,3H). 607.3 93 8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(4- fluorophenyl)-3,3- bis(hydroxymethyl)- 10-(trifluoromethyl)- 3,4-dihydro- 2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6- one 1431

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.28- 7.24 (m, 1H), 7.07 (t, J =8.8 Hz, 1H), 6.65-6.59 (m, 1H), 6.43-6.38 (m, 1H), 5.78 (dd, J = 10.4Hz, 1.6 Hz, 1H), 5.46-5.43 (m, 1H), 4.73- 4.58 (m, 2H), 4.21-4.16 (m,2H), 3.69-3.63 (m, 2H), 3.40-3.31 (m, 3H), 3.05- 3.01 (m, 1H), 1.61 (d,J = 6.8 Hz, 3H), 1.48 (d, J = 6.8 Hz, 3H). 632.3 96 (3S,10R)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(2,4- difluoro-5-methylphenyl)-3- ((methoxy- d3)methyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1432

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.28- 7.25 (m, 1H), 7.07 (t, J =8.8 Hz, 1H), 6.65-6.59 (m, 1H), 6.43-6.38 (m, 1H), 5.78 (dd, J = 10.4Hz, 1.6 Hz, 1H), 5.48-5.45 (m, 1H), 4.80- 4.43 (m, 2H), 4.21-4.16 (m,2H), 3.67-3.59 (m, 2H), 3.41-3.30 (m, 3H), 3.04- 3.00 (m, 1H), 1.52-1.61(m, 3H), 1.46 (d, J = 6.8 Hz, 3H). 632.3 55 (3S,10S)-7- ((3S,5R)-4-acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(2,4- difluoro-5-methylphenyl)-3- ((methoxy- d3)methyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one 1433

¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 1H), 7.25- 7.21 (m, 1H), 7.06 (t, J =8.8 Hz, 1H), 5.05-4.63 (m, 5H), 4.36 (d, J = 5.6 Hz, 3H), 3.89-3.64 (m,4H), 3.43-3.27 (m, 5H), 2.55- 2.42 (m, 1H), 1.39-1.16 (m, 9H). 644.2 70(S)-8′-((2S,5R)-4- (Acryloyl-d₃)-2,5- dimethylpiperazin-1-yl)-11′-(5-chloro- 2,4- difluorophenyl)- 10′- (trifluoromethyl)-2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]-6′- one 1434

¹H NMR (400 MHz, CDCl₃) δ 7.83 (s, 1H), 7.28- 7.25 (m, 1H), 7.05 (t, J =8.8 Hz, 1H), 5.08-4.62 (m, 5H), 4.36 (d, J = 6.4 Hz, 3H), 3.93-3.59 (m,4H), 3.45-3.32 (m, 5H), 2.57- 2.44 (m, 1H), 1.40-1.25 (m, 9H). 644.2 82(R)-8′-((2S,5R)-4- (Acryloyl-d₃)-2,5- dimethylpiperazin-1-yl)-11′-(5-chloro- 2,4- difluorophenyl)- 10′- (trifluoromethyl)-2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]-6′- one 1435

¹H NMR (400 MHz, MeOH-d₄) δ 8.08-7.83 (m, 1H), 7.67-7.22 (m, 2H),6.96-6.68 (m, 1H), 6.28 (dd, J = 16.6, 4.9 Hz, 1H), 5.81 (t, J = 8.9 Hz,1H), 5.12-4.93 (m, 1H), 4.85- 4.14 (m, 4H), 4.14-3.46 (m, 7H), 3.30-3.13(m, 1H), 3.04-2.81 (m, 1H), 1.90- 1.64 (m, 2H), 1.63-1.31 (m, 6H). 669.284 8′-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin- 1-yl)-11′-(5-chloro-2,4- difluorophenyl)- 10′- (trifluoromethyl)- 2,3,5,6-tetrahydro-2′H,4′H,6′H- spiro[pyran-4,3′- [1,4]thiazepino[2,3, 4-ij]quinazolin]-6′-one 1436

685.0 81 8′-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1-yl)-11′-(5-bromo- 2,4- difluorophenyl)- 10′- (trifluoromethyl)-2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]-6′- one 1437

¹H NMR (400 MHz, CDCl₃) δ 8.17-8.15 (m, 1H), 7.30-7.21 (m, 1H),7.08-7.03 (m, 1H), 6.62 (dd, J = 16.8 Hz, 10.4 Hz, 1H), 6.44-6.40 (m,1H), 5.79 (d, J = 10.4 Hz, 1H), 4.75-4.58 (m, 4H), 4.38-4.32 (m, 1H),4.23-4.13 (m, 2H), 3.82- 3.78 (m, 1H), 3.67-3.61 (m, 2H), 3.54-3.39 (m,3H), 2.83-2.69 (m, 3H), 1.65- 1.62 (m, 3H), 1.49-1.46 (m, 3H). 659.3 878-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-11-(5-chloro- 2,4-difluorophenyl)- 3,3- bis(hydroxymethyl)- 10- (trifluoromethyl)-3,4-dihydro- 2H,6H- [1,4]thiazepino[2,3, 4-ij]quinazolin-6- one 1438

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.28- 7.27 (m, 1H), 7.07 (t, J =8.8 Hz, 1H), 6.65-6.59 (m, 1H), 6.40 (dd, J = 2.0 Hz, J = 16.8 Hz, 1H),5.77 (dd, J = 2.0 Hz, J = 10.4 Hz, 1H), 5.40-5.37 (m, 1H), 5.20- 5.06(m, 1H), 4.79-4.56 (m, 2H), 4.20-4.17 (m, 2H), 3.50-3.46 (m, 1H), 3.40-3.30 (m, 2H) 3.10-2.96 (m, 4H), 2.92-2.78 (m, 1H), 2.66-2.47 (m, 2H),2.18- 1.98 (m, 2H), 1.60 (d, J = 7.2 Hz, 3H), 1.47 (d, J = 6.8 Hz, 3H).686.2 54 (3S,10S)-7- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-chloro- 2,4- difluorophenyl)-3- (((S)-3- fluoropyrrolidin-1-yl)methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1439

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.29- 7.27 (m, 1H), 7.07 (t, J =8.8 Hz, 1H), 6.65-6.59 (m, 1H), 6.40 (dd, J = 2.0 Hz, J = 16.8 Hz, 1H),5.77 (dd, J = 2.0 Hz, J = 10.4 Hz, 1H), 5.41-5.34 (m, 1H), 5.20- 5.06(m, 1H), 4.80-4.52 (m, 2H), 4.20-4.16 (m, 2H), 3.50-3.47 (m, 1H), 3.38-3.30 (m, 2H), 3.13-3.00 (m, 4H), 2.95-2.84 (m, 1H), 2.60-2.58 (m, 2H),2.17- 1.99 (m, 2H), 1.60 (d, J = 6.8 Hz, 3H), 1.48 (d, J = 6.8 Hz, 3H).686.2 73 (3S,10R)-7- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-chloro- 2,4- difluorophenyl)-3- (((S)-3- fluoropyrrolidin-1-yl)methyl)-9- (trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1440

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.28-7.25 (m, 1H), 7.03 (t, J =8.8 Hz, 1H), 6.66-6.59 (m, 1H), 6.40 (dd, J = 2.0 Hz, J = 16.4 Hz, 1H),5.76 (dd, J = 2.0 Hz, J = 10.4 Hz, 1H), 4.80-4.52 (m, 4H), 4.17-4.14 (m,2H), 3.34-3.08 (m, 5H), 2.73- 2.72 (m, 4H), 1.91-1.73 (m, 4H), 1.57-1.48(m, 6H). 668.3 51 (3S,11S)-8- ((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-11-(5-chloro- 2,4- difluorophenyl)-3-(pyrrolidin-1-yl) 10- (trifluoromethyl)- 3,4-dihydro-[1,4]thiazepino[2,3, 4-ij]quinazolin-6- one 1441

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.26-7.24 (m, 1H), 7.04 (t, J =8.8 Hz, 1H), 6.66-6.59 (m, 1H), 6.40 (d, J = 16.0 Hz, 1H), 5.76 (d, J =20 Hz, 1H), 4.89-4.45 (m, 4H), 4.14-4.13 (m, 2H), 3.42-3.15 (m, 5H),2.86- 2.53 (m, 4H), 1.90-1.73 (m, 4H), 1.55-1.43 (m, 6H). 668.3 79(3S,11R)-8- ((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro- 2,4- difluorophenyl)-3- (pyrrolidin-1-yl) 10-(trifluoromethyl)- 3,4-dihydro- 2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6- one 1442

¹H NMR (400 MHz, CDCl₃) δ 8.16-8.14 (m, 1H), 7.22-7.12 (m, 1H),7.06-6.92 (m, 2H), 6.66- 6.60 (m, 1H), 6.44-6.40 (m, 1H), 5.81-5.78 (m,1H), 4.76-4.70 (m, 1H), 4.66- 4.63 (m, 1H), 4.39-4.34 (m, 1H), 4.24-4.14(m, 2H), 3.80-3.76 (m, 1H), 3.67- 3.60 (m, 2H), 3.54-3.39 (m, 3H),2.90-2.65 (m, 3H), 1.65-1.63 (m, 3H), 1.49- 1.46 (m, 3H). 625.2 938-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-11-(2,4-difluorophenyl)- 3,3- bis(hydroxymethyl)- 10- (trifluoromethyl)-3,4-dihydro- 2H,6H- [1,4]thiazepino[2,3, 4-ij]quinazolin-6- one 1443

673.2 85 (3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-bromo- 2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1444

¹H NMR and NOESY analysis: ¹H NMR (400 MHz, MeOH-d₄) δ 8.13 (s, 1H),7.08 (t, J = 10.0 Hz, 1H), 6.90-6.72 (m, 2H), 6.29 (dd, J = 16.6, 2.0Hz, 1H), 5.80 (dd, J = 10.5, 2.0 Hz, 1H), 5.41-5.28 (m, 1H), 4.83-4.50(m, 2H), 4.33 (d, J = 13.8 Hz, 1H), 4.25 (d, J = 13.6 Hz, 1H), 3.73 (t,J = 9.2 Hz, 1H), 3.61 (dd, J = 9.2, 4.7 Hz, 1H), 3.48 (dd, J = 13.5, 4.8Hz, 1H), 3.44- 3.33 (m, 2H), 3.40 (s, 3H), 3.13 (dd, J = 13.8, 2.9 Hz,1H), 1.58 (d, J = 6.9 Hz, 611.2 90 (3S)-7-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin- 1-yl)-10-(2,4- difluoro-5- hydroxyphenyl)-3-(methoxymethyl)- 9-(trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 3H), 1.42 (d, J = 6.9 Hz, 3H);1445

¹H NMR (400 MHz, MeOH-d₄) δ 7.97 (d, J = 2.9 Hz, 1H), 7.64 (t, J = 7.5Hz, 1H), 7.31 (t, J = 8.9 Hz, 1H), 6.81 (ddd, J = 30.6, 16.7, 10.6 Hz,1H), 6.28 (ddd, J = 16.7, 5.6, 1.9 Hz, 1H), 5.81 (ddd, J = 10.2, 7.7,1.9 Hz, 1H), 4.86-4.60 (m, 3H), 4.55-4.46 (m, 1H), 4.45 (dd, J = 6.4,2.6 Hz, 2H), 4.39-4.15 (m, 1H), 3.96-3.33 (m, 6H), 1.49- 1.30 (m, 6H);685.0 95 (R)-8′-((2S,5R)-4- Acryloyl-2,5- dimethylpiperazin-1-yl)-11′-(5-bromo- 2,4- difluorophenyl)- 10′- (trifluoromethyl)-2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]-6′- one 1446

¹H NMR (400 MHz, MeOH-d₄) δ 7.96 (s, 1H), 7.69-7.53 (m, 1H), 7.32 (t, J= 9.0 Hz, 1H), 6.81 (ddd, J = 21.5, 16.7, 10.7 Hz, 1H), 6.28 (ddd, J =16.7, 7.5, 2.0 Hz, 1H), 5.81 (ddd, J = 10.7, 6.6, 1.9 Hz, 1H), 4.87-4.59(m, 3H), 4.55-4.46 (m, 1H), 4.45 (d, J = 6.4 Hz, 2H), 4.33-4.15 (m, 1H),3.97- 3.72 (m, 2H), 3.69-3.44 (m, 3H), 1.47-1.30 (m, 6H); 685.0 45(S)-8′-((2S,5R)-4- Acryloyl-2,5- dimethylpiperazin- 1-yl)-11′-(5-bromo-2,4- difluorophenyl)- 10′- (trifluoromethyl)- 2′H,4′H,6′H-spiro[oxetane-3,3′- [1,4]thiazepino[2,3, 4-ij]quinazolin]-6′- one 1447

¹H NMR (400 MHz, MeOH-d₄) δ 8.15 (s, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.35(t, J = 8.9 Hz, 1H), 6.84 (dd, J = 16.7, 10.6 Hz, 1H), 6.29 (dd, J =16.7, 2.0 Hz, 1H), 5.80 (dd, J = 10.6, 2.0 Hz, 1H), 5.43-5.32 (m, 1H),4.86-4.52 (m, 2H), 4.35 (d, J = 13.6 Hz, 1H), 4.26 (d, J = 13.6 Hz, 1H),3.69 (t, J = 9.1 Hz, 1H), 3.60 (dd, J = 9.2, 4.9 Hz, 1H), 3.52 (dd, J =13.6, 4.7 Hz, 1H), 3.47- 3.35 (m, 2H), 3.39 (s, 3H), 3.17 (dd, J = 13.7,3.0 Hz, 1H), 1.56 (d, J = 6.9 Hz, 3H), 1.42 (d, J = 6.9 Hz, 3H). 673.297 (3S,10R)-7- ((3S,5R)-4- Acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-bromo- 2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1448

¹H NMR (400 MHz, MeOH-d₄) δ 8.15 (s, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.34(t, J = 9.0 Hz, 1H), 6.84 (dd, J = 16.7, 10.6 Hz, 1H), 6.29 (dd, J =16.7, 2.0 Hz, 1H), 5.80 (dd, J = 10.6, 2.0 Hz, 1H), 5.41-5.31 (m, 1H),4.86-4.51 (m, 2H), 4.33 (d, J = 13.7 Hz, 1H), 4.26 (d, J = 13.4 Hz, 1H),3.75 (t, J = 9.2 Hz, 1H), 3.62 (dd, J = 9.2, 4.8 Hz, 1H), 3.49 (dd, J =13.5, 4.7 Hz, 1H), 3.45- 3.36 (m, 2H), 3.40 (s, 3H), 3.15 (dd, J = 13.7,2.9 Hz, 1H), 1.57 (d, J = 7.1 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H). 673.295 (3S,10S)-7- ((3S,5R)-4- Acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-bromo- 2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1449

¹H NMR (400 MHz, CDCl₃) δ 8.03-8.01 (m, 2H), 6.65-6.58 (m, 1H),6.49-6.38 (m, 2H), 5.79- 5.75 (m, 1H), 5.41-5.38 (m, 1H), 5.08 (s, 2H),4.77-4.45 (m, 2H), 4.18-4.15 (m, 2H), 3.76-3.64 (m, 2H), 3.40- 3.28 (m,6H), 2.99-2.90 (m, 1H), 1.50-1.42 (m, 6H). 701.1 94 (3S)-7-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(6-amino- 3-iodopyridin-2-yl)-3- (methoxymethyl)- 9-(trifluoromethyl)- 2,3-dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1450

¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.22- 7.18 (m, 4H), 6.66-6.59(m, 1H), 6.41 (d, J = 16.8 Hz, 1H), 5.78 (d, J = 10.8 Hz, 1H), 5.06-4.87(m, 1H), 4.87-4.50 (m, 4H), 4.17 (t, J = 14.8 Hz, 2H), 3.57-2.90 (m,6H), 2.41-2.33 (m, 2H), 2.14-1.90 (m, 2H), 1.56- 1.52 (m, 6H). 630.3 96(S)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin- 1-yl)-11-(4-fluorophenyl)-3-(2- oxopyrrolidin-1- yl)-10- (trifluoromethyl)-3,4-dihydro- 2H,6H- [1,4]thiazepino[2,3, 4-ij]quinazolin-6- one 1451

¹H NMR (400 MHz, CDCl₃) δ 8.13-8.07 (m, 1H), 7.19 (q, J = 8.4 Hz, 1H),7.08-6.93 (m, 2H), 6.64 (dd, J = 16.8 Hz, 10.8 Hz, 1H), 6.41 (dd, J =16.8 Hz, 1.6 Hz, 1H), 5.78 (dd, J = 10.8 Hz, 1.6 Hz, 1H), 5.29-5.18 (m,1H), 4.92- 4.42 (m, 2H), 4.27-4.12 (m, 2H), 3.40-3.24 (m, 2H), 3.15-3.02(m, 2H), 1.95- 1.78 (m, 2H), 1.63 (d, J = 7.2 Hz, 3H), 1.49 (d, J = 7.2Hz, 3H), 0.97 (t, J = 7.2 Hz, 3H). 579 95 (3S)-7-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin- 1-yl)-10-(2,4- difluorophenyl)-3-ethyl-9- (trifluoromethyl)- 2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1452

¹H NMR (400 MHz, MeOH-d₄) δ 8.16 (s, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.31(t, J = 8.9 Hz, 1H), 6.83 (dd, J = 16.7, 10.6 Hz, 1H), 6.29 (dd, J =16.7, 2.0 Hz, 1H), 5.80 (dd, J = 10.6, 2.0 Hz, 1H), 5.18-4.92 (m, 1H),4.88-4.51 (m, 4H), 4.44 (dd, J = 6.4, 3.0 Hz, 2H), 4.25 (d, J = 13.5 Hz,2H), 3.65-3.50 (m, 2H), 3.49- 3.33 (m, 3H), 1.50 (dd, J = 19.2, 6.8 Hz,6H). 685 97 8′-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11′-(5-bromo- 2,4- difluorophenyl)- 10′- (trifluoromethyl)-2′H,4′H,6′H- spiro[oxetane-3,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]-6′- one 1453

¹H NMR (400 MHz, MeOH-d₄) δ 7.94 (s, 1H), 6.95 (ddd, J = 11.5, 9.1, 2.8Hz, 1H), 6.90-6.73 (m, 1H), 6.69 (q, J = 10.2, 9.6 Hz, 1H), 6.28 (dd, J= 16.9, 5.8 Hz, 1H), 5.87-5.74 (m, 1H), 4.86-4.57 (m, 3H), 4.56- 3.98(m, 5H), 3.97-3.37 (m, 5H), 1.54-1.22 (m, 6H). 622.1 95 8′-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin- 1-yl)-11′-(5-amino- 2,4-difluorophenyl)- 10′- (trifluoromethyl)- 2′H,4′H,6′H-spiro[oxetane-3,3′- [1,4]thiazepino[2,3, 4-ij]quinazolin]-6′- one 1454

¹H NMR (400 MHz, MeOH-d₄) δ 7.95 (s, 1H), 7.04 (ddd, J = 11.4, 9.1, 3.0Hz, 1H), 6.90-6.68 (m, 2H), 6.34-6.20 (m, 1H), 5.80 (ddd, J = 9.8, 7.2,1.9 Hz, 1H), 4.87-4.56 (m, 4H), 4.55-4.38 (m, 3H), 4.37- 3.96 (m, 2H),3.95-3.36 (m, 5H), 1.53-1.19 (m, 6H). 623.1 92 8′-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin- 1-yl)-11′-(2,4- difluoro-5-hydroxyphenyl)- 10′- (trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′-[1,4]thiazepino[2,3, 4-ij]quinazolin]-6′- one 1455

¹H NMR (400 MHz, MeOH-d₄) δ 8.52 (br s, 0.5H), 8.05-7.84 (m, 1H),7.77-7.64 (m, 0.5H), 7.40- 7.22 (m, 1H), 6.94-6.68 (m, 1H), 6.28 (dd, J= 16.7, 6.2 Hz, 1H), 5.81 (dd, J = 10.7, 7.3 Hz, 1H), 5.11-5.00 (m, 1H),4.71-3.50 (m, 12H), 3.04-2.84 (m, 1H), 1.88- 1.67 (m, 2H), 1.66-1.30 (m,8H). 713.0 66 8′-((2S,5R)-4- Acryloyl-2,5- dimethylpiperazin-1-yl)-11′-(5-bromo- 2,4- difluorophenyl)- 10′- (trifluoromethyl)-2,3,5,6-tetrahydro- 2′H,4′H,6′H- spiro[pyran-4,3′- [1,4]thiazepino[2,3-4-ij]quinazolin]-6′- one

Z. Select Experimental Procedures for Compounds 2000 to 2109 Example2044a:(3S,11R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-oneExample 2044b:(3S,11S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

Step 1: tert-butyl(2S,6R)-4-((S)-11-chloro-3-hydroxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

To a solution of tert-butyl(2S,6R)-4-((S)-3-(benzyloxy)-11-chloro-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(1.17 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5mL) and trifluoromethanesulfonic acid (11.7 mmol). The mixture wasstirred at 25° C. for 2 hours and the volatiles were removed underreduced pressure to afford a residue that was redissolved indichloromethane (10 mL) and treated with di-tert-butyl dicarbonate (5.87mmol) and diisopropylethylamine (11.7 mmol). The reaction was stirred atroom temperature for 24 hours, the insoluble materials were filtered offand the solvent removed under reduced pressure. Purification of thiscrude by preparative-TLC (65% ethyl acetate in hexanes) afforded thetitle compound as light yellow solid in 56% yield.

MS (ESI) m/z=549.0 [M+H]+

Step 2: tert-butyl(2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

To a 0° C. solution of tert-butyl(2S,6R)-4-((S)-11-chloro-3-hydroxy-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(0.31 mmol) and 2-fluoropyrimidine (0.62 mmol) in tetrahydrofuran (2 mL)was added cesium carbonate (0.62 mmol). The mixture was stirred at 60°C. for 2 hours and quenched by the addition of water. The aqueous layerwas extracted with ethyl acetate three times and the combined organiclayers were washed with brine and dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The resulting residuewas purified by preparative-TLC (65% ethyl acetate in hexanes) to affordthe title compound in 65% yield as a colorless semisolid.

MS (ESI) m/z=627.0 [M+H]+

Step 3: tert-Butyl(2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

A solution of tert-butyl(2S,6R)-4-((S)-11-choro-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(0.19 mmol), (5-chloro-2,4-difluorophenyl)boronic acid (0.48 mmol),tetrakis(triphenylphosphine) palladium(0) (0.02 mmol) and potassiumphosphate (0.57 mmol) in toluene (5 mL) and water (0.1 mL) was stirredat 100° C. for 12 hours. The reaction was quenched with water andextracted with ethyl acetate twice. The combined organic layers wereconcentrated under reduced pressure to afford a residue that waspurified by semi-preparative reverse phase HPLC. The title compound wasisolated in 42% yield as a white solid.

MS (ESI) m/z=739.0 [M+H]+

Step 4:(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

A solution of tert-butyl(2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(0.04 mmol) in dichloromethane (2 mL) was treated with trifluoroaceticacid (0.5 mL). After 1 hour the volatiles were removed under reducedpressure to afford the title compound in 96% yield as a yellow oil. Thismaterial was used in the next step without further purification.

MS (ESI) m/z=639.0 [M+H]+

Step 5:(3S,11R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(2044a) and(3S,11S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(2044b)

To a solution of(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(0.04 mmol) in dichloromethane (2 mL) was added triethylamine (0.012mmol) and prop-2-enoyl chloride (0.06 mmol). The mixture was stirred atroom temperature for 30 minutes and was concentrated under reducedpressure. The resulting residue was purified by semi-preparative reversephase HPLC to afford compounds 2044a and 2044b as a 1:1 mixture ofdiastereomers. The separation of these diastereomers was carried out bySFC (DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um), 35% ethanol in CO2, 3mL/min using a photodiode-array detector).

Compound 2044a: Rt=0.53 min. MS (ESI) m/z=693.0 [M+H]+

¹H NMR (400 MHz, CDCl₃) δ 8.53 (d, J=4.8 Hz, 2H), 8.10 (s, 1H), 7.31 (t,J=7.6 Hz, 1H), 7.04 (t, J=8.8 Hz, 1H), 6.99 (t, J=4.8 Hz, 1H), 6.63 (dd,J=10.4, 16.8 Hz, 1H), 6.42 (dd, J=1.6, 16.4 Hz, 1H), 5.83-5.67 (m, 2H),5.22-4.44 (m, 4H), 4.18 (d, J=13.2 Hz, 2H), 3.68-3.47 (m, 1H), 3.46-3.24(m, 3H), 1.64-1.54 (m, 6H).

Compound 2044b: Rt=0.73 min. MS (ESI) m/z=693.0 [M+H]+

¹H NMR (400 MHz, CDCl₃) δ 8.54 (d, J=4.8 Hz, 2H), 8.10 (s, 1H),7.31-7.27 (m, 1H), 7.07 (t, J=8.8 Hz, 1H), 6.99 (t, J=4.8 Hz, 1H), 6.63(dd, J=10.4, 16.8 Hz, 1H), 6.42 (dd, J=2.0, 16.8 Hz, 1H), 5.82-5.62 (m,2H), 5.07-4.40 (m, 4H), 4.18 (d, J=13.2 Hz, 2H), 3.57-3.31 (m, 4H),1.91-1.54 (m, 6H).

Example 2066:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-bromo-2,4-difluorophenyl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

Step 1:(S)-2-((1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-yl)oxy)pyrimidine

(S)-1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-ol (25.5mmol) was added to a 0° C. suspension of NaH (30.8 mmol) in THF (30 mL).After 30 minutes, 2-chloropyrimidine (30.6 mmol) was added and themixture was stirred at room temperature for 6 hours. The reaction wasquenched with water and extracted with ethyl acetate three times. Thecombined organic layers were washed with brine, dried over sodiumsulfate and concentrated to afford a residue that was purified by silicagel column chromatography (0-30% ethyl acetate in hexanes) to afford thetitle compound in 98% yield as a yellow oil.

MS (ESI) m/z=689.2 [M+H]+

Step 2:(S)-3-((tert-butyldiphenylsilyl)oxy)-2-(pyrimidin-2-yloxy)propane-1-thiol

To a 0° C. mixture of(S)-2-((1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-yl)oxy)pyrimidine(39 mmol) in dichloromethane (120 mL) and trifluoroacetic acid (30 mL),Et₃SiH (78 mmol) was added and after 5 minutes the reaction was stoppedby the addition of water. The mixture was extracted with dichloromethanethree times and the combined organic layers were dried over sodiumsulfate, concentrated and the resulting residue was purified by silicagel column chromatography (0-2% methanol in dichloromethane). The titlecompound was isolated in 59% yield as a colorless oil.

MS (ESI) m/z=447.1 [M+Na]+

Step 3:(S)-8-((3-((tert-butyldiphenylsilyl)oxy)-2-(pyrimidin-2-yloxy)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to Example 100, step 9 ofPCT/US2020/065966 where(S)-3-((tert-butyldiphenylsilyl)oxy)-2-(pyrimidin-2-yloxy)propane-1-thiolwas substituted in place of 2-mercaptoethan-1-ol. The title compound wasisolated in 65% yield as a white solid.

MS (ESI) m/z=687.1 [M+H]+

Step 4:(S)-7-Chloro-8-((3-hydroxy-2-(pyrimidin-2-yloxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

To a mixture of(S)-8-((3-((tert-butyldiphenylsilyl)oxy)-2-(pyrimidin-2-yloxy)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(8 g) in THF (80 mL) was added a 1M solution of tetrabutylammoniumfluoride in THF (35 mmol) and the mixture was stirred at roomtemperature for 4 hours. Evaporation of volatiles under reduced pressureafforded a residue that was washed with water and filtered. The filtercake was washed with ethyl acetate. The title compound was isolated in57% yield as an off-white solid.

MS (ESI) m/z=449.0 [M+H]+

Step 5:(S)-11-Chloro-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to Example 100, step 10 ofPCT/US2020/065966 where(S)-7-chloro-8-((3-hydroxy-2-(pyrimidin-2-yloxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas substituted in place of7-(2,4-difluorophenyl)-8-((2-hydroxyethyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.The title compound was isolated in 72% yield as a white solid.

MS (ESI) m/z=431.0 [M+H]+

Step 6: tert-Butyl(2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21 ofPCT/US2020/065966 where(S)-11-chloro-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dioneand (2R,6S)-2,6-dimethyl piperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 87% yield as a yellow solid.

MS (ESI) m/z=627.1 [M+H]+

Step 7: tert-Butyl(2S,6R)-4-((3S)-11-(5-amino-2,4-difluorophenyl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

A mixture of tert-butyl(2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(0.64 mmol),2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(1.15 mmol), RuPhos Pd G4 (0.19 mmol) and K₃PO₄ (1.91 mmol) in dioxane(5 mL) and water (0.5 mL) was stirred at 80° C. for 1 hour. The reactionwas diluted with ethyl acetate and washed with brine, the organic layerwas separated and dried over sodium sulfate, filtered and concentratedto afford a crude that was purified by reverse phase chromatography. Thetitle compound was isolated in 30% yield as a yellow solid.

MS (ESI) m/z=720.0 [M+H]+

Step 8: tert-Butyl(2S,6R)-4-((3S)-11-(5-bromo-2,4-difluorophenyl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

A mixture of tert-butyl(2S,6R)-4-((3S)-11-(5-amino-2,4-difluorophenyl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(0.17 mmol) and BuBr2 (0.22 mmol) in acetonitrile (2.5 mL) was treatedwith tert-butyl nitrite (0.22 mmol) and the reaction was stirred for 30minutes. The reaction was diluted with ethyl acetate and washed withbrine, the organic layer was separated and dried over sodium sulfate,filtered and concentrated to afford a crude that was purified by reversephase chromatography. The title compound was isolated in 54% yield as ayellow solid.

MS (ESI) m/z=783.0 [M+H]+

Step 9:(3S)-11-(5-bromo-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 1, step 4 wheretert-Butyl(2S,6R)-4-((3S)-11-(5-bromo-2,4-difluorophenyl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylatewas substituted in place of tert-butyl(2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate.The title compound was isolated in 95% yield as a white solid

MS (ESI) m/z=682.9/685.0 [M+H]+

Step 10:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-bromo-2,4-difluorophenyl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 1, step 4 where(3S)-11-(5-bromo-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one.The title compound was isolated in 31% yield as a white solid.

MS (ESI) m/z=736.9/739.0 [M+H]+

Example 2048 (also Example 2055):(3S,11R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(pyrimidin-2-ylamino)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

Step 1: tert-Butyl(2S,6R)-4-((S)-3-(((benzyloxy)carbonyl)amino)-11-chloro-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to Example 100, step 21 ofPCT/US2020/065966 where benzyl(S)-(11-chloro-6,8-dioxo-10-(trifluoromethyl)-3,4,7,8-tetrahydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-3-yl)carbamateand (2R,6S)-2,6-dimethyl piperazine were substituted in place of10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(6H)-dioneand octahydrothieno[3,4-b]pyrazine 6,6-dioxide. The title compound wasisolated in 64% yield as a yellow solid.

MS (ESI) m/z=682.1 [M+H]+

Step 2:(S)-3-Amino-11-chloro-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

To a solution of tert-butyl(2S,6R)-4-((S)-3-(((benzyloxy)carbonyl)amino)-11-chloro-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(1.61 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid(67.5 mmol) and trifluoromethanesulfonic acid (8.06 mmol) at 0° C. Themixture was stirred at room temperature for two hours. The mixture wasfiltered and the filtrate was concentrated under reduced pressure toafford a residue that was purified by silica gel chromatography (10-50%ethyl acetate in hexanes). The title compound was isolated in 99% yieldand was used into the next step without further purification.

MS (ESI) m/z=448.0 [M+H]+

Step 3:(S)-11-Chloro-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-ylamino)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

To a solution of(S)-3-amino-11-chloro-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(0.22 mmol) in DMF (1 mL) was added diisopropylethylamine (0.67 mmol)and 2-fluoropyrimidine (0.31 mmol). The mixture was stirred at roomtemperature for 24 hours and it was diluted with ethyl acetate andwater. The organic layer was washed with water and brine, dried oversodium sulfate and concentrated to afford a residue that was purified bypreparative HPLC. The title compound was isolated in 34% yield as ayellow solid.

MS (ESI) m/z=526.0 [M+H]+

Step 4:(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-ylamino)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 1, step 3 where(S)-11-chloro-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-ylamino)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of tert-butyl(2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate.The title compound was isolated in 99% yield as a yellow solid

MS (ESI) m/z=638.0 [M+H]+

Step 5:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(pyrimidin-2-ylamino)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 1, step 5 where(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-ylamino)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-onewas substituted in place of(3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one.The separation of this diastereomer was carried out by SFC (DAICELCHIRALPAK AD (250 mm*30 mm, 10 um), 40% isopropanol in CO2, 3 mL/minusing a photodiode-array detector) in 15% yield as a white solid.Rt=1.28 min. MS (ESI) m/z=692.0 [M+H]+

1H NMR (400 MHz, CDCl3) δ, 8.44-8.19 (m, 2H), 8.12 (s, 1H), 7.27-7.23(m, 2H), 7.06 (br t, J=8.8 Hz, 1H), 6.80-6.59 (m, 2H), 6.42 (dd, J=1.6,16.8 Hz, 1H), 5.79 (dd, J=1.6, 10.4 Hz, 1H), 5.12-4.61 (m, 4H),4.59-4.34 (m, 1H), 4.27-4.15 (m, 2H), 3.77-3.57 (m, 1H), 3.46-3.35 (m,2H), 3.32-3.13 (m, 1H), 1.55 (br s, 6H).

Example 2065:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-bromo-2,4-difluorophenyl)-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 2066, steps 1-10where 2-fluoropyrazine was substituted in place of 2-chloropyrimidineduring step 1.

MS (ESI) m/z=737.1 [M+H]+

1H NMR (400 MHz, CDCl₃) δ 8.25 (s, 1H), 8.15 (s, 1H), 8.11-8.07 (m, 2H),7.46-74.42 (m, 1H), 7.26 (m, 1H), 6.63 (dd, J=10.4, 16.8 Hz, 1H), 6.42(dd, J=1.6, 16.4 Hz, 1H), 5.83-5.67 (d, J=10.4 Hz, 2H), 4.90-4.50 (m,4H), 4.25 (m, 2H), 3.68-3.24 (m, 4H), 1.75-1.30 (m, 6H).

Example 2064:(3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-bromo-2,4-difluorophenyl)-3-(pyridin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to Example 2066, steps 1-10where 2-chloropyridine was substituted in place of 2-chloropyrimidineduring step 1.

MS (ESI) m/z=736.0 [M+H]+

1H NMR (400 MHz, CDCl3) δ=8.25-8.01 (m, 2H), 7.75-7.59 (m, 1H),7.48-7.36 (m, 1H), 7.10-6.91 (m, 2H), 6.89-6.75 (m, 1H), 6.63 (dd,J=16.6, 10.6, 1H), 6.42 (dd, J=16.6, 2.0, 1H), 5.93-5.71 (m, 2H),5.04-4.48 (m, 4H), 4.28-4.06 (m, 2H), 3.67-3.25 (m, 4H), 1.71-1.36 (m,6H).

Example 2009:(S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-10-(2,4,6-trifluorophenyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

(R)-1-mercapto-3-methoxypropan-2-ol (2)

To a mixture of (S)-2-(methoxymethyl)oxirane (50 g, 568.2 mmol) intetrahydrofuran (800 mL) was added 1,1,1,3,3,3-hexamethyldisilathiane(119.4 g, 681.8 mmol) and tetrabutylammonium fluoride (1.0 M intetrahydrofuran, 170.6 mL, 170.5 mmol) at 0° C. The mixture was stirredat room temperature for 2 hours. After completion, the mixture waspoured into water (3000 mL), extracted with ethyl acetate (800 mL×3).The combined organic phases were washed with brine (800 mL) and driedover anhydrous sodium sulfate. After filtration and concentration, theresidue was purified by silica gel column with petroleum ether/ethylacetate=3/1 to afford (R)-1-mercapto-3-methoxypropan-2-ol (2) (70.0 g,crude) as a colorless oil.

1H NMR (300 MHz, CDCl3) δ 3.86-3.82 (m, 1H), 3.49-3.46 (m, 1H),3.41-3.37 (m, 4H), 2.71-2.64 (m, 1H), 1.55-1.50 (m, 1H).

(R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(4)

To a solution of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (20 g,51.2 mmol) in dioxane (800 mL), potassium carbonate (21.2 g, 153.6mmol), (R)-1-mercapto-3-methoxypropan-2-ol (11.26 g, 92.1 mmol),4,5-Bis(diphenyl-phosphino)-9,9-dimethylxanthene (5.93 g, 10.24 mmol)and Tris(dibenzylideneacetone) dipalladium (4.7 g, 5.1 mmol) were added.The mixture was stirred at 55° C. under nitrogen atmosphere for 18hours. After completion, the insoluble was filtered out. Afterconcentration, the residue was adjusted to PH=4 with acetic acid andextracted with ethyl acetate (1000 mL), washed with brine (500 mL). Theorganic phase was concentrated and recrystallized(dichloromethane/methanol=1/10). The mixture was filtered and collectedfilter cake to afford(R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(14 g, yield: 71%) as a white solid. MS (ESI) m/z 385.0 [M+H]⁺.

(S)-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(5)

To a mixture of(R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(4) (34.4 g, 89.5 mmol) and triphenylphosphine (35.2 g, 134.3 mmol) intetrahydrofuran (500 mL) was added diethyl azodicarboxylate (23.3 g,134.3 mmol) at 0° C. The mixture was stirred at 0° C. for 45 min. Aftercompletion, the mixture was poured into ice-water (300 mL) and extractedwith ethyl acetate (500 mL×3). Concentrated and the residue wasrecrystallized (dichloromethane/methanol=1/10), the mixture was filteredand collected filter cake to afford(S)-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(5) (24.0 g, 73% yield) as a white solid. MS (ESI): m/z 367.0 [M+H]⁺.

(2S,6R)-tert-butyl4-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6)

To a mixture of(S)-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(5) (10 g, 27.32 mmol) and potassium carbonate (37.7 g, 273.2 mmol) inacetonitrile (500 mL) was added 4-methylbenzenesulfonic anhydride (13.4g, 40.98 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min andat 30° C. for 4 hours. After completion, (2S,6R)-tert-butyl2,6-dimethylpiperazine-1-carboxylate (11.7 g, 54.64 mmol) was added intothe reaction solution. The reaction mixture was stirred at 0° C. for 2hours. After completion, the mixture was filtered through a Celite pad,and the filtrate was purified by chromatography column(dichloromethane/methanol=100/1 to 30/1) to afford (2S,6R)-tert-butyl4-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6) (15 g, crude) as a pale-white solid. MS (ESI) m/z 563.5 [M+H]⁺.

(2S,6R)-tert-butyl4-((S)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-10-(2,4,6-trifluorophenyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(7)

To a solution of (2S,6R)-tert-butyl4-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6) (280 mg, 0.5 mmol), tripotassium phosphate (400 mg, 1.5 mmol) andChloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(80 mg, 0.1 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was addedanother solution of (2,4,6-trifluorophenyl)boronic acid (1.58 g, 10mmol) and Chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(80 mg, 0.1 mmol) in 1,4-dioxane (5 mL) at 85° C. under nitrogenatmosphere. After completion, the mixture was diluted withtetrahydrofuran (50 mL) and filtered. After concentration, the residuewas purified by silica gel column chromatography(dichloromethane/methanol=100/1 to 30/1) to afford (2S,6R)-tert-butyl4-((S)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-10-(2,4,6-trifluorophenyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(7) (64 mg, yield: 20%) as a yellow solid. MS (ESI) m/z 659.6 [M+H]⁺.

(S)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-10-(2,4,6-trifluorophenyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a cooled mixture of (2S,6R)-tert-butyl4-((S)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-10-(2,4,6-trifluorophenyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(7) (64 mg, 0.1 mmol) in dichloromethane (4 ml) was addedtrifluoroacetic acid (2 mL) at 0° C. The reaction solution was stirredat room temperature for 3 hours. After completion, the mixture wasconcentrated, the residue was purified by column(dichloromethane/methanol=15:1) to afford(S)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-10-(2,4,6-trifluorophenyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(54 mg, yield: 90%) as a yellow solid. MS (ESI) m/z 559.6 [M+H]⁺.

(S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-10-(2,4,6-trifluorophenyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9)

To a mixture of(S)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-10-(2,4,6-trifluorophenyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8) (54 mg, 0.1 mmol) and triethyl amine (30 mg, 0.3 mmol) indichloromethane (2 ml) was added acrylic anhydride (13 mg, 0.1 mmol) at0° C. The mixture was stirred at 0° C. for 3 hours. After completion,the mixture was poured into ice-water (30 mL) and extracted with ethylacetate (20 mL×3). After Concentration and the residue was purified bychromatography column (dichloromethane/methanol=60/1 to 30/1) to afford(S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-10-(2,4,6-trifluorophenyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9) (6 mg, yield: 10%) as a white solid. MS (ESI) m/z 613.6 [M+H]⁺.

¹H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 6.82 (t, J=7.2 Hz, 2H), 6.62(dd, J=10.8 Hz, J=16.8 Hz, 1H), 6.40 (dd, J=1.6 Hz, J=16.4 Hz, 1H), 5.77(dd, J=1.6 Hz, J=10.4 Hz, 1H), 5.50-5.45 (m, 1H), 4.85-4.52 (m, 2H),4.22-4.16 (m, 2H), 3.67-3.60 (m, 2H), 3.40 (s, 3H), 3.37-3.30 (m, 3H),3.07 (dd, J=2.8 Hz, J=13.2 Hz, 1H), 1.62 (d, J=6.8 Hz, 3H), 1.47 (d,J=7.2 Hz, 3H).

Example 2014:(3S,10R)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(6-fluoro-1-methyl-1H-indazol-7-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(6)

(E)-2-(3-Bromo-2,4-difluorobenzylidene)-1-methylhydrazin-1-ium chloride(1)

3-Bromo-2,4-difluorobenzaldehyde (4.0 g, 18.1 mmol, 1 equiv) was addedto a 250 mL round-bottom flask under a N₂ atmosphere and dissolved in1,2-dichloroethane (180 mL). Next, tert-butyl1-methylhydrazine-1-carboxylate (3.8 mL, 25.34 mmol, 1.4 equiv, den.0.985 g/mL) was added by syringe and the reaction mixture was stirred atroom temperature. After 2.5 h, the solvent was removed by rotaryevaporation (full conversion determined by LC-MS). Next, 4N HCl in1,4-dioxane (45 mL) was added in portions (ca. 10 min) to the resultingcolorless liquid. The reaction mixture was stirred at room temperaturefor 1 h. The white precipitate was collected using a Büchner funnel,washed with THF (100 mL) and dried under high vacuum to afford(E)-2-(3-bromo-2,4-difluorobenzylidene)-1-methylhydrazin-1-ium chlorideas a pale-yellow solid (1) (6.13 g, 97%): ¹H NMR (400 MHz, DMSO-d₆) δ8.91-8.30 (br s, 1H), 7.61-7.51 (m, 1H), 7.35-7.24 (m, 1H), 7.14-7.05(m, 1H), 2.84 (s, 2H), 2.59 (s, 1H); LRMS-ESI (m/z) [M+H]⁺ calculatedfor C₈H₈BrF₂N₂ 248.98, found 249.0.

7-Bromo-6-fluoro-1-methyl-1H-indazole (2)

Sodium hydride (60 wt % in mineral oil, 756 mg, 18.9 mmol, 3.6 equiv)was added to a 100 mL round-bottom flask under a N₂ atmosphere andpurged with N₂ for 30 min prior to the addition of DMF (20 mL). Next,(E)-2-(3-bromo-2,4-difluorobenzylidene)-1-methylhydrazin-1-ium chloride(1) (1.5 g, 5.25 mmol, 1 equiv) was added to the flask at roomtemperature in two portions. After 2.5 h, additional sodium hydride (60wt % in mineral oil, 210 mg, 5.25 mmol, 1 equiv) was added. Afteranother 1 h, additional sodium hydride (60 wt % in mineral oil, 53 mg,1.31 mmol, 0.25 equiv) was added. After 30 min, the reaction mixture wascooled 0° C. and saturated aqueous NH₄Cl (ca. 1 mL) was slowly added tothe mixture. The resulting solution was transferred to a separatoryfunnel using EtOAc (200 mL) and the organic layer was washed with H₂O(50 mL, 2×). The aqueous phases were combined and extracted with EtOAc(200 mL). The organic layers were combined and dried over Na₂SO₄ and thesolvent was removed by rotary evaporation. The crude material waspurified by flash column chromatography using an Isolera One Biotageinstrument (0-25% EtOAc/hexanes, 25 g column, 0% (5 CV), 0-5% (10 CV),5-25% (1 CV), 25% (10 CV), to provide 2 (760 mg, 63%) as anorange/yellow solid: TLC (5% EtOAc/hexanes) R_(f)=0.31; ¹H NMR (400 MHz,CDCl₃) δ 8.04 (s, 1H), 7.44 (dd, J=8.1, 4.5 Hz, 1H), 6.65 (t, J=8.6 Hz,1H), 4.42 (s, 3H); LRMS-ESI (m/z) [M+H]⁺ calculated for C₈H₇BrFN₂228.98, found 229.0.

6-Fluoro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(3)

Compound 2 (200 mg, 0.87 mmol, 1 equiv) was dissolved in 1,4-dioxane(12.5 mL, 0.07 M) in a 50 mL bomb-flask. The resulting mixture waspurged with N₂ for 30 min prior to the addition of Pd(dppf)Cl₂ (64 mg,0.087 mmol, 10 mol %), KOAc (171 mg, 1.74 mmol, 2 equiv), and B₂(pin)₂(265 mg, 1.044 mmol, 1.2 equiv), and then bubbled with N₂ for anadditional 5 min. The flask placed on a heated block at 90° C. Anadditional 200 mg batch was set up using the same procedure. After 1 h,both batches were combined and filtered through Celite 545 using DCM(ca. 50 mL) and the solvent was removed by rotary evaporation. The crudematerial was purified by flash column chromatography using an IsoleraOne Biotage instrument (0-20% EtOAc/hexanes, 25 g column, 0% (5 CV),0-5% (10 CV), 5% (5 CV), 5-20% (1 CV), 20% (5 CV)), to provide 3 (215mg, 45%) as a yellow solid: TLC (10% EtOAc/hexanes) R_(f)=0.22; ¹H NMR(400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.86 (dd, J=7.8, 5.8 Hz, 1H), 6.77 (dd,J=9.6, 7.8 Hz, 1H), 4.32 (s, 3H), 1.40 (s, 12H); LRMS-ESI (m/z) [M+H]⁺calculated for C₁₄H₁₉BFN₂O₂ 277.15, found 277.2.

tert-Butyl(2S,6R)-4-((3S,10R)-10-(6-fluoro-1-methyl-1H-indazol-7-yl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(5)

Compound 4 (50 mg, 0.089 mmol, 1 equiv) was dissolved in 1,4-dioxane andH₂O (3.2 mL, 0.8 mL, respectively, 0.02 M). The resulting mixture waspurged with N₂ for 30 min prior to the addition of RuPhos Pd G4 (7.6 mg,0.0089 mmol, 10 mol %), K₃PO₄ (57 mg, 0.267 mmol, 3 equiv), and6-fluoro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(3) (174 mg, 0.63 mmol, 7 equiv). The microwave vial was fitted with acrimp-top cap, bubbled with N₂ for an additional 5 min, and placed on aheated block at 80° C. The resulting reaction mixture was homogenous.After 5 h, the vial was removed from the heating block, allowed to cool,and the solvent was removed by rotary evaporation. The crude materialwas purified by preparative thin-layer chromatography (Silica Gel 60F₂₅₄, 0.5 mm, 20×20 cm, 2 plates) using 3% MeOH/CH₂Cl₂ to provide 30 mgof 5 as a yellow oil in decent purity. The material was used in thesubsequent step: LRMS-ESI (m/z) [M+H]⁺ calculated for C₃₂H₃₇F₄N₆O₄S677.25, found 677.3.

(3S,10R)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(6-fluoro-1-methyl-1H-indazol-7-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(6)

Boc deprotection and acrylation were carried out using the sameprocedures described in other examples. The title compound 6 wasobtained as a yellow solid (1.53 mg, 5% over two-steps).

¹H NMR (400 MHz, MeOH-d₄) δ 8.22 (s, 1H), 8.16 (s, 1H), 7.18 (dd, J=8.0,4.8 Hz, 1H), 6.97 (dd, J=9.7, 8.0 Hz, 1H), 6.85 (dd, J=16.7, 10.5 Hz,1H), 6.30 (dd, J=16.6, 2.0 Hz, 1H), 5.81 (dd, J=10.6, 2.0 Hz, 1H),5.39-5.31 (m, 1H), 4.84-4.46 (m, 3H), 4.39 (d, J=13.8 Hz, 1H), 4.30 (d,J=13.6 Hz, 1H), 3.73-3.60 (m, 2H), 3.56 (s, 3H), 3.55-3.38 (m, 3H), 3.36(s, 2H), 3.35-3.33 (m, 1H), 3.15 (dd, J=13.7, 3.0 Hz, 1H), 1.60 (d,J=7.0 Hz, 3H), 1.47-1.39 (m, 3H); LRMS-ESI (m/z) [M+H]⁺ calculated forC₃₀H₃₁F₄N₆O₃S 631.21, found 631.2.

Example 2018 (also Example 2027):(3S)-7-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluoro-5-hydroxyphenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(3)

tert-Butyl(2S,6R)-4-((3S)-10-(2,4-difluoro-5-hydroxyphenyl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(2)

Compound 1 (50 mg, 0.089 mmol, 1 equiv) was dissolved in 1,4-dioxane andH₂O (3.2 mL, 0.8 mL, respectively, 0.022 M). The resulting mixture waspurged with N₂ for 30 min prior to the addition of RuPhos Pd G4 (7.6 mg,0.0089 mmol, 10 mol %), K₃PO₄ (56.7 mg, 0.267 mmol, 3 equiv), and(2,4-difluoro-5-hydroxyphenyl)boronic acid (46.4 mg, 0.267 mmol, 3equiv). The microwave vial was fitted with a crimp-top cap, bubbled withN₂ for an additional 5 min, and placed on a heated block at 80° C. Theresulting reaction mixture was homogenous. After 1 h, the vial wasremoved from the heating block, allowed to cool, and the solvent wasremoved by rotary evaporation (full conversion determined by LC-MS). Thecrude material was purified by flash column chromatography using anIsolera One Biotage instrument (0-75% EtOAc/hexanes, 10 g column, 0% (5CV), 0-50% (10 CV), 50% (5 CV), 50-75% (2 CV), 75% (10 CV)) to affordthe desired product 2 as a yellow solid (36 mg, 62%): TLC (50%EtOAc/hexanes) R_(f)=0.15/0.08 (atropisomers); ¹H NMR (400 MHz, CDCl₃,mixture of both atropisomers) δ 8.05 (s, 0.5H), 8.00 (s, 0.5H), 6.98(ddd, J=10.2, 8.6, 4.7 Hz, 1H), 6.85 (dd, J=9.3, 6.8 Hz, 0.5H), 6.72 (t,J=8.1 Hz, 0.5H), 5.53-5.37 (m, 1H), 4.47-4.25 (m, 2H), 4.23-3.92 (m,2H), 3.75-3.50 (m, 2H), 3.45-2.98 (m, 4H), 3.38 (s, 3H), 1.54 (t, J=7.0Hz, 3H), 1.50 (s, 9H), 1.35 (dd, J=9.7, 6.9 Hz, 3H); LRMS-ESI (m/z)[M+H]⁺ calculated for C₃₀H₃₄F₅N₄O₅S 657.22, found 657.2.

(3S)-7-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluoro-5-hydroxyphenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(3)

Compound 2 (33 mg, 0.05 mmol, 1 equiv) was dissolved in anhydrous CH₂Cl₂(3 mL) in a 20 dr vial followed by the addition of CF₃COOH (1 mL) atroom temperature and capped. After 30 min, the reaction was determinedto be complete by LC-MS and the solvent was removed by rotaryevaporation. The resulting solid was dissolved in MeOH, loaded onto aHyperSep SCX plug, and flushed with MeOH (ca. 30 mL). Next, the desiredproduct was eluted with 1N NH₃ in MeOH (ca. 30 mL) and collected. Thesolvent was removed by rotary evaporation and the solid was dissolved in2-MeTHF (2.5 mL) and H₂O (2.5 mL). The reaction mixture was cooled to 0°C. and K₂CO₃ (21 mg, 0.15 mmol, 3 equiv) was added. Next, acryloylchloride (6.1 μL, 0.075 mmol, 1.5 equiv) was added by syringe in ca. 3portions at 0° C. over 1 h. After 1.5 h, the solvent was removed byrotary evaporation. The crude material was dissolved in MeOH, filteredwith a 0.45 μM PTFE plug, and purified by preparative RP-HPLC (Luna 5 μMC18(2) 100 Å, 100×30 mm, 5-95% MeCN+0.1% (v/v) HCOOH and H₂O+0.1% (v/v)HCOOH). The product fractions were collected, and the solvent wasremoved by rotary evaporation, followed by lyophilization (−91 to −71°C.; <0.01 mbar) in deionized water to afford 3 (4.2 mg, 14%) as a whitesolid. Note: Regioselectivity and acrylamide formation was confirmed by¹H NMR and NOESY analysis: ¹H NMR (400 MHz, MeOH-d₄) δ 8.13 (s, 1H),7.08 (t, J=10.0 Hz, 1H), 6.90-6.72 (m, 2H), 6.29 (dd, J=16.6, 2.0 Hz,1H), 5.80 (dd, J=10.5, 2.0 Hz, 1H), 5.41-5.28 (m, 1H), 4.83-4.50 (m,2H), 4.33 (d, J=13.8 Hz, 1H), 4.25 (d, J=13.6 Hz, 1H), 3.73 (t, J=9.2Hz, 1H), 3.61 (dd, J=9.2, 4.7 Hz, 1H), 3.48 (dd, J=13.5, 4.8 Hz, 1H),3.44-3.33 (m, 2H), 3.40 (s, 3H), 3.13 (dd, J=13.8, 2.9 Hz, 1H), 1.58 (d,J=6.9 Hz, 3H), 1.42 (d, J=6.9 Hz, 3H); LRMS-ESI (m/z) [M+H]⁺ calculatedfor C₂₈H₂₈F₅N₄O₄S 611.18, found 611.2.

Example 2028 and 2029:(3S,10R)-7-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-bromo-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(P1) and(3S,10S)-7-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-bromo-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(P2)

tert-Butyl(2S,6R)-4-((3S)-10-(5-amino-2,4-difluorophenyl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(2)

Compound 1 (73 mg, 0.13 mmol, 1 equiv) was dissolved in 1,4-dioxane andH₂O (3.0 mL, 0.75 mL, respectively, 0.035 M). The resulting mixture waspurged with N₂ for 30 min prior to the addition of RuPhos Pd G4 (11 mg,0.013 mmol, 10 mol %), K₃PO₄ (83 mg, 0.39 mmol, 3 equiv), and2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (99mg, 0.39 mmol, 3 equiv). The microwave vial was fitted with a crimp-topcap, bubbled with N₂ for an additional 5 min, and placed on a heatedblock at 80° C. The resulting reaction mixture was homogenous. After 2h, the vial was removed from the heating block, allowed to cool, and thesolvent was removed by rotary evaporation (full conversion determined byLC-MS). The crude material was purified by flash column chromatographyusing an Isolera One Biotage instrument (0-100% EtOAc/hexanes, 10 gcolumn, 0% (5 CV), 0-75% (10 CV), 75% (5 CV), 75-100% (1 CV), 100% (5CV)), to provide 2 (53.4 mg, 63%) as a beige solid: TLC (50%EtOAc/hexanes) R_(f)=0.17/0.11 (both atropisomers); ¹H NMR (400 MHz,CDCl₃) δ 8.05 (s, 1H), 6.97-6.87 (m, 1H), 6.63 (t, J=8.1 Hz, 1H),5.56-5.36 (m, 1H), 4.49-4.28 (m, 2H), 4.23-4.03 (m, 2H), 3.73-3.52 (m,2H), 3.44-3.14 (m, 7H), 3.01 (d, J=13.6 Hz, 1H), 1.53 (d, J=7.1 Hz, 3H),1.49 (s, 9H), 1.36 (d, J=6.8 Hz, 3H); LRMS-ESI (m/z) [M+H]⁺ calculatedfor C₃₀H₃₅F₅N₅O₄S 656.23, found 656.2.

tert-Butyl(2S,6R)-4-((3S)-10-(5-bromo-2,4-difluorophenyl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ji]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(3)

CuBr₂ (23 mg, 0.099 mmol, 1.2 equiv) was added to a 5 mL microwave vial,purged with N₂ for 30 min, and dissolved in MeCN (600 μL). Next,tert-butyl nitrite (8.5 μL, 0.078 mmol, 0.95 equiv, den. 0.867 g/mL) wasadded at room temperature resulting in a green/blue solution. Compound 2(54 mg, 0.082 mmol, 1 equiv) as a solution in MeCN (2.0 mL) under a N₂atmosphere was then added by syringe to the copper solution over ca. 5min. After 1 h, the reaction mixture was diluted with EtOAc and filteredthrough Celite 545 using EtOAc (50 mL). The solvent was removed byrotary evaporation and the crude material was purified by flash columnchromatography using an Isolera One Biotage instrument (0-6%MeOH/CH₂Cl₂, 10 g column, 0% (5 CV), 0-3% (10 CV), 3% (5 CV), 3-4% (1CV), 4% (5 CV), 4-6% (1 CV), 6% (5 CV)), to provide 3 (49 mg, 88%) as ayellow solid: TLC (3% MeOH/CH₂Cl₂) R_(f)=0.34; ¹H NMR (400 MHz, CDCl₃) δ8.07 (s, 1H), 7.41 (t, J=7.3 Hz, 1H), 7.05 (td, J=8.5, 2.7 Hz, 1H),5.52-5.39 (m, 1H), 4.44-4.31 (m, 2H), 4.22-4.05 (m, 2H), 3.71-3.56 (m,2H), 3.45-3.33 (m, 4H), 3.32-3.18 (m, 2H), 3.01 (dt, J=13.7, 3.7 Hz,1H), 1.53 (d, J=7.0 Hz, 3H), 1.50 (s, 9H), 1.37 (t, J=6.4 Hz, 3H);LRMS-ESI (m/z) [M+H]⁺ calculated for C₃₀H₃₃BrF₅N₄O₄S 719.13, found719.2.

(3S,10R)-7-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-bromo-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(P1) and(3S,10S)-7-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-bromo-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(P2)

Compound 3 (49 mg, 0.068 mmol, 1 equiv) was dissolved in anhydrousCH₂Cl₂ (3 mL) in a 20 dr vial followed by the addition of CF₃COOH (1 mL)at room temperature and capped. After 30 min the solvent was removed byrotary evaporation. The reaction mixture was dissolved in MeOH, loadedonto a HyperSep SCX plug, and flushed with MeOH (ca. 30 mL). Next, thedesired intermediate was eluted with 1N NH₃ in MeOH (ca. 30 mL) andcollected. The solvent was removed by rotary evaporation and the crudematerial was dissolved in anhydrous CH₂Cl₂ (6 mL) in a 20 dr vial andcapped. Next, DIPEA (11.8 μL, 0.068 mmol, 1 equiv) was added by syringeto the reaction at room temperature followed by acryloyl chloride (5.5μL, 0.068 mmol, 1 equiv) and capped. After 10 min, the reaction wasdetermined to be complete by LC-MS and the solvent was removed by rotaryevaporation. The crude material was dissolved in MeOH, filtered with a0.45 μM PTFE plug, and purified by preparative RP-HPLC (Luna 5 μM C18(2)100 Å, 100×30 mm, 5-95% MeCN+0.1% (v/v) HCOOH and H₂O+0.1% (v/v) HCOOH).The product fractions were collected, and the solvent was removed byrotary evaporation, followed by lyophilization (−91 to −71° C.; <0.01mbar) in deionized water to afford 23.2 mg (51% yield) of P1 and P2 as abeige solid. The atropisomers were separated by chiral preparative HPLCon a CHIRALPAK® AD-H column to afford P1 (10.3 mg, 22%) and P2 (11.0 mg,24%) as white solids.

P1: ¹H NMR (400 MHz, MeOH-d₄) δ 8.15 (s, 1H), 7.66 (t, J=7.4 Hz, 1H),7.34 (t, J=9.0 Hz, 1H), 6.84 (dd, J=16.7, 10.6 Hz, 1H), 6.29 (dd,J=16.7, 2.0 Hz, 1H), 5.80 (dd, J=10.6, 2.0 Hz, 1H), 5.41-5.31 (m, 1H),4.86-4.51 (m, 2H), 4.33 (d, J=13.7 Hz, 1H), 4.26 (d, J=13.4 Hz, 1H),3.75 (t, J=9.2 Hz, 1H), 3.62 (dd, J=9.2, 4.8 Hz, 1H), 3.49 (dd, J=13.5,4.7 Hz, 1H), 3.45-3.36 (m, 2H), 3.40 (s, 3H), 3.15 (dd, J=13.7, 2.9 Hz,1H), 1.57 (d, J=7.1 Hz, 3H), 1.42 (d, J=7.0 Hz, 3H); LRMS-ESI (m/z)[M+H]⁺ calculated for C₂₈H₂₇BrF₅N₄O₃S 673.09, found 673.2.

P2: ¹H NMR (400 MHz, MeOH-d₄) δ 8.15 (s, 1H), 7.60 (t, J=7.5 Hz, 1H),7.35 (t, J=8.9 Hz, 1H), 6.84 (dd, J=16.7, 10.6 Hz, 1H), 6.29 (dd,J=16.7, 2.0 Hz, 1H), 5.80 (dd, J=10.6, 2.0 Hz, 1H), 5.43-5.32 (m, 1H),4.86-4.52 (m, 2H), 4.35 (d, J=13.6 Hz, 1H), 4.26 (d, J=13.6 Hz, 1H),3.69 (t, J=9.1 Hz, 1H), 3.60 (dd, J=9.2, 4.9 Hz, 1H), 3.52 (dd, J=13.6,4.7 Hz, 1H), 3.47-3.35 (m, 2H), 3.39 (s, 3H), 3.17 (dd, J=13.7, 3.0 Hz,1H), 1.56 (d, J=6.9 Hz, 3H), 1.42 (d, J=6.9 Hz, 3H); LRMS-ESI (m/z)[M+H]⁺ calculated for C₂₈H₂₇BrF₅N₄O₃S 673.09, found 673.2.

Example 2030 and 2031:(3S,10R)-7-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-amino-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one,Formate Salt (P1) and(3S,10S)-7-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-amino-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one,Formate Salt (P2)

tert-Butyl(2S,6R)-4-((3S)-10-(5-amino-2,4-difluorophenyl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(2)

Compound 1 (50 mg, 0.089 mmol, 1 equiv) was dissolved in 1,4-dioxane andH₂O (2.5 mL, 0.5 mL, respectively, 0.030 M). The resulting mixture waspurged with N₂ for 30 min prior to the addition of RuPhos Pd G4 (7.6 mg,0.0089 mmol, 10 mol %), K₃PO₄ (57 mg, 0.267 mmol, 3 equiv), and2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (68mg, 0.267 mmol, 3 equiv). The microwave vial was fitted with a crimp-topcap, bubbled with N₂ for an additional 5 min, and placed on a heatedblock at 80° C. The resulting reaction mixture was homogenous. After 1.5h, the vial was removed from the heating block, allowed to cool, and thesolvent was removed by rotary evaporation (full conversion determined byLC-MS). The crude material was purified by flash column chromatographyusing an Isolera One Biotage instrument (0-100% EtOAc/hexanes, 10 gcolumn, 0% (5 CV), 0-50% (10 CV), 50% (5 CV), 50-100 (5 CV), 100% (5 CV)to afford the desired product (2) as a yellow solid (49 mg, 84%): TLC(50% EtOAc/hexanes) R_(f)=0.18, 0.10 (atropisomers); ¹H NMR (400 MHz,CDCl₃) δ 8.06 (s, 1H), 6.96 (t, J=9.5 Hz, 1H), 6.91-6.75 (m, 1H),5.52-5.38 (m, 1H), 4.46-4.28 (m, 2H), 4.21-4.14 (m, 2H), 3.73-3.53 (m,2H), 3.45-3.37 (m, 3H), 3.37-3.17 (m, 3H), 3.07-2.92 (m, 1H), 1.53 (d,J=6.9 Hz, 3H), 1.50 (s, 9H), 1.37 (dd, J=6.9, 4.3 Hz, 3H); LRMS-ESI(m/z) [M+H]⁺ calculated for C₃₀H₃₅F₅N₅O₄S 656.23, found 656.3.

(3S,10R)-7-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-amino-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one,Formate Salt (P1) and(3S,10S)-7-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-amino-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one,Formate Salt (P2)

Compound 2 (49 mg, 0.075 mmol, 1 equiv) was dissolved in anhydrousCH₂Cl₂ (3 mL) in a 20 dr vial followed by the addition of CF₃COOH (1 mL)at room temperature and capped. After 20 min, the solvent was removed byrotary evaporation. The reaction mixture was dissolved in MeOH, loadedonto a HyperSep SCX plug, and flushed with MeOH (ca. 30 mL). Next, thedesired intermediate was eluted with 1N NH₃ in MeOH (ca. 30 mL) andcollected. The solvent was removed by rotary evaporation and the crudematerial was dissolved in anhydrous CH₂Cl₂ (3 mL) in a 20 dr vial andcapped. Next, DIPEA (13.1 μL, 0.075 mmol, 1 equiv) was added by syringeto the reaction at room temperature followed by acryloyl chloride (6.1μL, 0.075 mmol, 1 equiv) as a DCM (1 mL) solution over (ca. 20 min) andcapped. After 10 min, the reaction was determined to be complete byLC-MS and the solvent was removed by rotary evaporation. The crudematerial was dissolved in MeOH, filtered with a 0.45 μM PTFE plug, andpurified by preparative RP-HPLC (Luna 5 μM C18(2) 100 Å, 100×30 mm,25-95% MeCN+0.1% (v/v) HCOOH and H₂O+0.1% (v/v) HCOOH). The productfractions were collected, and the solvent was removed by rotaryevaporation, followed by lyophilization (−91 to −71° C.; <0.01 mbar) indeionized water to afford 9.6 mg (20% yield) of P1 and 8.8 mg (18%yield) of P2. Note: Regioselectivity and acrylamide formation wasconfirmed by ¹H NMR and NOESY analysis.

P1: ¹H NMR (400 MHz, MeOH-d₄) δ 8.12 (s, 1H), 6.98 (dd, J=11.1, 9.1 Hz,1H), 6.84 (dd, J=16.7, 10.6 Hz, 1H), 6.71 (dd, J=9.5, 7.1 Hz, 1H), 6.29(dd, J=16.7, 2.0 Hz, 1H), 5.84-5.76 (m, 1H), 5.41-5.29 (m, 1H),4.85-4.47 (m, 2H), 4.32 (d, J=13.8 Hz, 1H), 4.25 (d, J=13.7 Hz, 1H),3.72 (d, J=9.1 Hz, 1H), 3.61 (dd, J=9.1, 4.7 Hz, 1H), 3.47 (dd, J=13.6,4.6 Hz, 1H), 3.43-3.33 (m, 2H), 3.39 (s, 3H), 3.12 (dd, J=13.7, 2.9 Hz,1H), 1.58 (d, J=6.9 Hz, 3H), 1.42 (d, J=6.9 Hz, 3H); LRMS-ESI (m/z)[M+H]⁺ calculated for C₂₈H₂₉F₅N₅O₃S 610.19, found 610.2.

P2: ¹H NMR (400 MHz, MeOH-d₄) δ 8.12 (s, 1H), 6.98 (dd, J=11.0, 9.1 Hz,1H), 6.84 (dd, J=16.6, 10.6 Hz, 1H), 6.67 (dd, J=9.5, 7.1 Hz, 1H), 6.29(dd, J=16.6, 2.1 Hz, 1H), 5.80 (dd, J=10.5, 2.0 Hz, 1H), 5.43-5.31 (m,1H), 4.85-4.50 (m, 2H), 4.33 (d, J=13.6 Hz, 1H), 4.25 (d, J=13.6 Hz,1H), 3.70 (t, J=9.1 Hz, 1H), 3.58 (dd, J=9.2, 4.9 Hz, 1H), 3.48 (dd,J=13.5, 4.7 Hz, 1H), 3.43-3.33 (m, 2H), 3.39 (s, 3H), 3.14 (dd, J=13.6,2.9 Hz, 1H), 1.57 (d, J=6.9 Hz, 3H), 1.42 (d, J=6.9 Hz, 3H); LRMS-ESI(m/z) [M+H]⁺ calculated for C₂₈H₂₉F₅N₅O₃S 610.19, found 610.2.

Example 2056 and 2057:(3S,10R)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluoro-5-iodophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(P1) and(3S,10S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluoro-5-iodophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(P2)

tert-Butyl(2S,6R)-4-((3S)-10-(5-amino-2,4-difluorophenyl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(2)

Compound 1 (60 mg, 0.107 mmol, 1 equiv) was dissolved in 1,4-dioxane andH₂O (2.5 mL, 0.5 mL, respectively, 0.036 M). The resulting mixture waspurged with N₂ for 30 min prior to the addition of RuPhos Pd G4 (9.1 mg,0.0107 mmol, 10 mol %), K₃PO₄ (68 mg, 0.321 mmol, 3 equiv), and2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (82mg, 0.321 mmol, 3 equiv). The microwave vial was fitted with a crimp-topcap, bubbled with N₂ for an additional 5 min, and placed on a heatedblock at 80° C. The resulting reaction mixture was homogenous. After 2h, the vial was removed from the heating block, allowed to cool, and thesolvent was removed by rotary evaporation (full conversion determined byLC-MS). The crude material was purified by flash column chromatographyusing an Isolera One Biotage instrument (0-100% EtOAc/hexanes, 10 gcolumn, 0% (5 CV), 0-75% (10 CV), 75% (5 CV), 75-100% (1 CV), 100% (5CV)), to provide 2 (70 mg, 99%) as an orange/brown oil: TLC (50%EtOAc/hexanes) R_(f)=0.17/0.11 (atropisomers); ¹H NMR (400 MHz, CDCl₃) δ8.05 (s, 1H), 6.97-6.87 (m, 1H), 6.63 (t, J=8.1 Hz, 1H), 5.56-5.36 (m,1H), 4.49-4.28 (m, 2H), 4.23-4.03 (m, 2H), 3.73-3.52 (m, 2H), 3.44-3.14(m, 7H), 3.01 (d, J=13.6 Hz, 1H), 1.53 (d, J=7.1 Hz, 3H), 1.49 (s, 9H),1.36 (d, J=6.8 Hz, 3H); LRMS-ESI (m/z) [M+H]⁺ calculated forC₃₀H₃₅F₅N₅O₄S 656.23, found 656.2.

tert-butyl(2S,6R)-4-((3S)-10-(2,4-difluoro-5-iodophenyl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(3)

CuI (24.4 mg, 0.128 mmol, 1.2 equiv) was added to a 5 mL microwave vial,purged with N₂ for 30 min, and dissolved in MeCN (0.5 mL). Next,tert-butyl nitrite (12.1 μL, 0.102 mmol, 0.95 equiv, den. 0.867 g/mL)was added at room temperature resulting in a yellow solution. Compound 2(70 mg, 0.107 mmol, 1 equiv) as a solution in MeCN (2.0 mL) under a N₂atmosphere was then added by syringe to the copper solution over ca. 5min. The reaction mixture was placed on a heated block at 60° C. andheated for 14 h. Next, the solution was diluted with EtOAc and filteredthrough Celite 545 using EtOAc (50 mL). The solvent was removed byrotary evaporation and the crude material was purified by flash columnchromatography using an Isolera One Biotage instrument (0-75%EtOAc/hexanes, 10 g column, 0% (5 CV), 0-50% (10 CV), 50% (5 CV), 50-75%(1 CV), 75% (5 CV)), to provide 3 (46 mg, 56%) as a yellow solid: TLC(50% EtOAc/hexanes) R_(f)=0.34/0.26 (atropisomers); ¹H NMR (400 MHz,CDCl₃) δ 8.07 (s, 1H), 7.62-7.54 (m, 1H), 7.06-6.93 (m, 1H), 5.54-5.39(m, 1H), 4.45-4.29 (m, 2H), 4.22-4.02 (m, 2H), 3.71-3.53 (m, 2H),3.44-3.40 (m, 1H), 3.39 (s, 3H), 3.38-3.21 (m, 3H), 3.07-2.95 (m, 1H),1.57-1.52 (m, 3H), 1.50 (s, 9H), 1.42-1.33 (m, 3H); LRMS-ESI (m/z)[M+H]⁺ calculated for C₃₀H₃₃F₅IN₄O₄S 767.12, found 767.2.

(3S,10R)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluoro-5-iodophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(P1) and(3S,10S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluoro-5-iodophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(P2)

Compound 3 (54 mg, 0.07 mmol, 1 equiv) was dissolved in anhydrous CH₂Cl₂(3 mL) in a 20 dr vial followed by the addition of CF₃COOH (1 mL) atroom temperature and capped. After 45 min the solvent was removed byrotary evaporation. The reaction mixture was dissolved in MeOH, loadedonto a HyperSep SCX plug, and flushed with MeOH (ca. 30 mL). Next, thedesired intermediate was eluted with 1N NH₃ in MeOH (ca. 30 mL) andcollected. The solvent was removed by rotary evaporation and the crudematerial was dissolved in anhydrous CH₂Cl₂ (3 mL) in a 20 dr vial andcapped. Next, DIPEA (12.2 μL, 0.07 mmol, 1 equiv) was added by syringeto the reaction at room temperature followed by acryloyl chloride (5.7μL, 0.07 mmol, 1 equiv) and capped. After 15 min, the reaction wasdetermined to be complete by LC-MS and the solvent was removed by rotaryevaporation. The crude material was dissolved in MeOH, filtered with a0.45 μM PTFE plug, and purified by preparative RP-HPLC (Luna 5 μM C18(2)100 Å, 100×30 mm, 25-95% MeCN+0.1% (v/v) HCOOH and H₂O+0.1% (v/v)HCOOH). The product fractions were collected, and the solvent wasremoved by rotary evaporation, followed by lyophilization (−91 to −71°C.; <0.01 mbar) in deionized water to afford 11 mg (22% yield) of P1 and8.5 mg (17% yield) of P2. P1 and P2 were further purified by chiralpreparative HPLC on a CHIRALPAK® AD-H column (30%2-isopropanol/heptane).

P1: ¹H NMR (400 MHz, MeOH-d₄) δ 8.14 (s, 1H), 7.78 (t, J=7.3 Hz, 1H),7.24 (t, J=8.8 Hz, 1H), 6.84 (dd, J=16.7, 10.6 Hz, 1H), 6.29 (d, J=16.0Hz, 1H), 5.80 (dd, J=10.5, 2.0 Hz, 1H), 5.42-5.30 (m, 1H), 4.84-4.51 (brs, 2H), 4.33 (d, J=13.3 Hz, 1H), 4.26 (d, J=13.5 Hz, 1H), 4.20 (s, 1H),3.80-3.66 (m, 1H), 3.65-3.56 (m, 1H), 3.55-3.42 (m, 2H), 3.41 (s, 3H),3.40-3.35 (m, 2H), 3.20-3.10 (m, 1H), 1.57 (d, J=6.8 Hz, 3H), 1.42 (d,J=6.9 Hz, 3H); LRMS-ESI (m/z) [M+H]⁺ calculated for C₂₈H₂₇F₅IN₄O₃S721.08, found 721.2.

P2: ¹H NMR (400 MHz, MeOH-d₄) δ 8.14 (s, 1H), 7.73 (t, J=7.4 Hz, 1H),7.25 (dd, J=9.4, 8.1 Hz, 1H), 6.84 (dd, J=16.7, 10.6 Hz, 1H), 6.29 (dd,J=16.7, 2.0 Hz, 1H), 5.80 (dd, J=10.6, 2.0 Hz, 1H), 5.43-5.31 (m, 1H),4.84-4.55 (m, 2H), 4.35 (d, J=13.5 Hz, 1H), 4.26 (d, J=13.5 Hz, 1H),4.18 (s, 1H), 3.69 (t, J=9.2 Hz, 1H), 3.59 (dd, J=9.3, 4.9 Hz, 1H), 3.51(dd, J=13.5, 4.8 Hz, 1H), 3.46-3.38 (m, 1H), 3.39 (s, 3H), 3.38-3.35 (m,1H), 3.17 (dd, J=13.6, 3.0 Hz, 1H), 1.57 (d, J=6.9 Hz, 3H), 1.42 (d,J=6.9 Hz, 3H); LRMS-ESI (m/z) [M+H]⁺ calculated for C₂₈H₂₇F₅IN₄O₃S721.08, found 721.2.

Example 2015:(S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

(R)-2,2-dimethyl-4-((trideuteriomethoxy)methyl)-1,3-dioxolane (2)

To a mixture of (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (20 g,151.4 mmol) in THF (350 mL) was added NaH (12.1 g, 302.7 mmol). Themixture was stirred at 0° C. to room temperature for 0.5 hour.Consequently, CD₃I (37.0 g, 237.2 mmol) was added. The mixture wasstirred at room temperature overnight. After completion, the mixture waspoured into NH₄Cl (300 mL), washed with ethyl acetate (200 mL×3). Theorganic phase was washed with water (100 mL) and dried over anhydroussodium sulfate, After filtration and concentration under reducepressure, compound (2) (13.0 g, crude) was obtained as yellow oil. ¹HNMR (400 MHz, CDCl₃) δ 4.31-4.24 (m, 1H), 4.07-4.04 (m, 1H), 3.72-3.68(m, 1H), 3.49-3.39 (m, 2H), 1.43 (s, 3H), 1.37 (s, 3H).

(S)-3-(trideuteriomethoxy)propane-1,2-diol (3)

The mixture of(R)-2,2-dimethyl-4-((trideuteriomethoxy)methyl)-1,3-dioxolane (2) (13.0g, 89.0 mmol, crude) and HCl (1200 mmol) in THF (100 mL) and water (100mL) was stirred at room temperature overnight. The solvent wasevaporated and the residue was purified by silica gel chromatographywith DCM/MEOH=20/1 to afford (S)-3-(trideuteriomethoxy)propane-1,2-diol(3) (4.7 g, 49.8 mmol, 50% yield) as yellow oil; ¹H NMR (400 MHz, CDCl₃)δ 3.82-3.78 (m, 1H), 3.55 (dd, J=4.4 Hz, 11.6 Hz, 1H), 3.49-3.45 (m,2H), 3.38 (dd, J=6.8 Hz, 10.4 Hz, 1H).

(R)-2-hydroxy-3-(trideuteriomethoxy)propyl 4-methylbenzenesulfonate (4)

To a mixture of (S)-3-methoxypropane-1,2-diol (3) (4.7 g, 43.1 mmol) andTEA (8.9 mL, 64.6 mmol) in DCM (60 mL) was added TsCl (6.5 g, 34.4 mmol)at 0° C. The mixture was stirred at room temperature overnight. Thesolvent was evaporated and the residue was purified by silica gelchromatography (2% MeOH in DCM) to affordt(R)-2-hydroxy-3-(trideuteriomethoxy)propyl 4-methylbenzenesulfonate (4)(7.7 g, crude) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=8.0Hz, 2H), 7.35 (d, 6.4 Hz, 2H), 4.08-3.95 (m, 3H), 3.43-2.45 (m, 2H).

(R)-1-mercapto-3-(trideuteriomethoxy)propan-2-ol (5)

The mixture of (R)-2-hydroxy-3-methoxypropyl 4-methylbenzenesulfonate(4) (7.7 g, 29.5 mmol, crude) and NaSH (7.09 g, 88.7 mmol) in EtOH (100mL) was stirred at room temperature 2 hours. The solvent was evaporatedand the residue was purified by silica gel column by PE/EA=1/1 to afford(R)-1-mercapto-3-(trideuteriomethoxy)propan-2-ol (5) (2.9 g, 15.2 mmol,crude) as yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 3.85-3.79 (m, 1H),3.51-3.41 (m, 2H), 2.73-2.59 (m, 2H), 1.47 (t, J=8.4 Hz, 1H).

(R)-7-chloro-8-((2-hydroxy-3-(trideuteriomethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (6)

The mixture of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (5.7 g,14.8 mmol), Pd2(dba)3 (1.3 g, 1.48 mmol), XantPhos (1.7 g, 2.96 mmol),(R)-1-mercapto-3-(trideuteriomethoxy)propan-2-ol (2.7 g, 22.24 mmol) andK₂CO₃ (6.13 g, 44.4 mmol) in dioxane (300 mL) was stirred under nitrogenatmosphere at 55° C. for overnight. After completion, the mixture wasconcentrated and the residue was purified by silica gel column withDCM/MeOH=20:1 to afford (R)-7-chloro-8-((2-hydroxy-3-(trideuteriomethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (6)(2.8 g, crude) as a light yellow solid. LC-MS: [M+H], m/z=388.5

(S)-10-chloro-3-((trifluoromethoxy)methyl)-9-(trideuteriomethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione (7)

To a mixture of (R)-7-chloro-8-((2-hydroxy-3-(trideuteriomethoxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (6)(2.8 g, 7.2 mmol) and triphenylphosphine (3.8 g, 14.4 mmol) in THF (50mL) was slowly added DEAD (2.5 g, 13.5 mmol) at 0° C. under nitrogenatmosphere. The mixture was stirred at room temperature for 1 hour. DCM(50 mL) was added. The organic phase was washed with water (50 mL×2).Dried over Na₂SO₄. the mixture was concentrated and the residue waspurified by silica gel column with PE/EA=0-50% to afford(S)-10-chloro-3-((trifluoromethoxy)methyl)-9-(trideuteriomethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione (7) (870mg, 2.24 mmol, yield: 31%) as a yellow solid. LC-MS: [M+H], m/z=370.2.

(2S,6R)-tert-butyl4-((S)-10-chloro-5-oxo-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(8)

To a solution of(S)-10-chloro-3-((trifluoromethoxy)methyl)-9-(trideuteriomethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione (7) (820mg, 2.16 mmol) and K₂CO₃ (2.98 g, 21.6 mmol) in ACN (20 mL) and DCM (20mL) was added P-Toluenesulfonic anhydride (1.40 g, 4.32 mmol). Themixture was stirred at room temperature for 5 hours. To the mixture wasadded (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (925 mg,4.32 mmol). The mixture was stirred at room temperature for 2 hours.After completion, the mixture was concentrated under reduced pressureand purified by silica gel column with DCM/EA=20%-80% to afford(2S,6R)-tert-butyl4-((S)-10-chloro-5-oxo-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(8) (680 mg, yield: 49%) as yellow solid. LC-MS: m/z 566.5 [M+H]⁺;

(2S,6R)-tert-butyl4-((S)-10-(4-fluorophenyl)-5-oxo-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(9)

To a solution of ((2S,6R)-tert-butyl4-((S)-10-chloro-5-oxo-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(8) (150 mg, 0.26 mmol) in dioxane (5 mL) and water (1 mL) was added(4-fluorophenyl)boronic acid (297 mg, 2.12 mmol), RuPhos Pd G2 (30 mg,0.03 mmol) and K3PO4 (692 m g, 2.6 mmol). The mixture was stirred at 75°C. under N2 for 2 hours. After completion, the mixture was poured intowater (2 mL), extracted with EtOAc (5 mL×3). The combined organic phaseswere washed with brine (5 mL) and dried over Na₂SO₄. After filtrationand concentration, the residue was purified by silica gel column usingdichloromethane/methanol=50:1 to afford the (2S,6R)-tert-butyl4-((S)-10-(4-fluorophenyl)-5-oxo-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(9) (160 mg, crude) as a yellow solid. MS (ESI) m/z 626.6 [M+H]+

(S)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(10)

To a solution of (2S,6R)-tert-butyl4-((S)-10-(4-fluorophenyl)-5-oxo-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(9) (160 mg, 0.25 mmol) in DCM (3 mL) was added TFA (1 mL) at 0° C. Themixture was stirred at room temperature for 1 hour. After completion,the mixture was concentrated under reduced pressure to afford(S)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(10) (150 mg, crude) as yellow solid. LC-MS: m/z 526.3 [M+H]+. 1H NMR(400 MHz, CDCl3) δ 7.78 (s, 1H), 7.21-7.17 (m, 4H), 5.43-5.37 (m, 1H),4.39 (d, J=12.4, 1H), 4.20 (d, J=11.6 Hz, 2H), 3.66-3.64 (m, 2H),3.33-3.29 (m, 1H), 3.21-3.13 (m, 1H), 2.96-2.92 (m, 3H), 2.72 (t, J=11.2Hz, 1H), 1.16-1.12 (m, 6H).

(S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(11)

To a solution of(S)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(10) (100 mg, 0.19 mmol) and Et₃N (28 mg, 0.28 mmol) in DCM (3 mL) wasadded acrylic anhydride (36 mg, 0.28 mmol) at 0° C. The mixture wasstirred at room temperature for 30 min. After completion, the mixturewas quenched with 1 mL of MeOH, concentrated under reduced pressure andpurified by C18 with 5-95% ACN in H2O to afford(S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(4-fluorophenyl)-3-((trideuteriomethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(11) (57 mg, 52% yield) as a white powder. LC-MS: m/z 580.2 [M+H]⁺; 1HNMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.23-7.15 (m, 4H), 6.62 (dd, J=10.4Hz, J=16.4 Hz, 1H), 6.41 (dd, J=1.6 Hz, J=16.8 Hz, 1H), 5.77 (dd, J=2.0Hz, J=10.4 Hz, 1H), 5.43-5.41 (m, 1H), 4.82-4.54 (m, 2H), 4.21-4.16 (m,2H), 3.69-3.62 (m, 2H), 3.39-3.29 (m, 3H), 2.98-2.94 (m, 1H), 1.62 (d,J=7.2 Hz, 3H), 1.47 (d, J=7.2 Hz, 3H).

Example 2004:(S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(3-chloro-4-fluorophenyl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

(S)-2-((methoxymethoxy)methyl)oxirane (2)

To a mixture of (R)-oxiran-2-ylmethanol (15 g, 202.7 mmol) andN,N-diisopropylethylamine (52.3 g, 405.4 mmol) in dichloromethane (200mL) was added bromo(methoxy)methane (32.7 g, 263.5 mmol). The mixturewas stirred at 0° C. to room temperature for 5 hours. After completion,the mixture was poured into dichloromethane (300 mL), washed with water(200 mL×3). The organic phase was washed with brine (100 mL) and driedover anhydrous sodium sulfate, After filtration and concentration, theresidue was purified by silica gel column with petroleum ether to afford(S)-2-((methoxymethoxy)methyl)oxirane (2) (25.00 g, crude) as colorlessoil; ¹H NMR (400 MHz, CDCl₃) δ 4.66 (d, J=1.2 Hz, 2H), 3.79 (dd, J=11.6Hz, 3.2 Hz, 1H), 3.51 (dd, J=11.6 Hz, 2.0 Hz, 1H), 3.38 (s, 3H),3.20-3.16 (m, 1H), 2.83-2.80 (m, 1H), 2.64 (dd, J=5.2 Hz, 2.8 Hz, 1H).

(R)-1-mercapto-3-(methoxymethoxy)propan-2-ol (3)

To a mixture of (S)-2-((methoxymethoxy)methyl)oxirane (2) (10 g, 84.7mmol) in tetrahydrofuran (250 mL) was added1,1,1,3,3,3-hexamethyldisilathiane (16.63 g, 93.2 mmol) andtetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 25 mL, 25 mmol)at 0° C. The mixture was stirred at room temperature for 2 hours. Aftercompletion, the mixture was concentrated under reduced pressure. Theresidue was purified by silica gel column with petroleum ether/ethylacetate=4/1 to afford (R)-1-mercapto-3-(methoxymethoxy)propan-2-ol (3)(2 g, yield: 16%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 4.66 (s,2H), 3.85-3.82 (m, 1H), 3.69-3.60 (m, 2H), 3.39 (s, 3H), 2.88 (brs, 1H),2.71-2.65 (m, 2H), 1.51 (t, J=8.8 Hz, 1H).

(R)-7-chloro-4-hydroxy-8-((2-hydroxy-3-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(4)

To a solution of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (1.86 g,4.77 mmol) in dioxane (40 mL) was added potassium carbonate (1.32 g,9.54 mmol), (R)-1-mercapto-3-(methoxymethoxy)propan-2-ol (1.09 g, 7.15mmol), 4,5-Bis(diphenyl-phosphino)-9,9-dimethylxanthene (413 mg, 0.72mmol) and Tris(dibenzylideneacetone) dipalladium (439 g, 0.48 mmol). Themixture was stirred at 60° C. under nitrogen atmosphere for 18 hours.After completion, the mixture was concentrated under reduced pressure.The residue was purified by silica gel column chromatography(dichloromethane/methanol=60/1) to afford(R)-7-chloro-4-hydroxy-8-((2-hydroxy-3-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(4) (1.33 g, yield: 67%) as pale yellow solid. MS (ESI) m/z 415.0[M+H]⁺.

(S)-10-chloro-7-hydroxy-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5)

To a mixture of(R)-7-chloro-4-hydroxy-8-((2-hydroxy-3-(methoxymethoxy)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(4) (1.33 g, 3.21 mmol) and triphenylphosphine (3.37 g, 12.85 mmol) intetrahydrofuran (500 ml) was added diethyl azodicarboxylate (2.23 g,12.85 mmol) at 0° C. The mixture was stirred at 0° C. for 45 min. Aftercompletion, the mixture was poured into ice-water (200 mL) and extractedwith ethyl acetate (200 mL×3). Concentrated and the residue was purifiedby C18 with 30-95% acetonitrile in water to afford(S)-10-chloro-7-hydroxy-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5) (1.1 g, yield: 87%) as a pale yellow solid. MS (ESI) m/z 397.0[M+H]⁺.

(2S,6R)-tert-butyl4-((S)-10-chloro-3-((methoxymethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6)

To a mixture of(S)-10-chloro-7-hydroxy-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(5) (300 mg, 0.76 mmol) and potassium carbonate (1.05 g, 7.6 mmol) inacetonitrile (10 mL) was added 4-methylbenzenesulfonic anhydride (620mg, 1.9 mmol) at 0° C. The mixture was stirred at room temperature for 4hours. After completion, (2R,6S)-tert-butyl2,6-dimethylpiperazine-1-carboxylate (650 mg, 3.04 mmol) was added intothe reaction solution. The reaction mixture was stirred at roomtemperature for 1 hour. After completion, the mixture was poured intoice-water (50 mL) and extracted with ethyl acetate (50 mL×3).Concentrated and the residue was purified by C18 column with 20-95%acetonitrile in water to afford (2S,6R)-tert-butyl4-((S)-10-chloro-3-((methoxymethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6) (345 mg, yield: 77%) as a yellow solid. MS (ESI) m/z 593.2 [M+H]⁺.

(2S,6R)-tert-butyl4-((S)-10-(3-chloro-4-fluorophenyl)-3-((methoxymethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(7)

To a solution of (2S,6R)-tert-butyl4-((S)-10-chloro-3-((methoxymethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(6) (200 mg, 0.34 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) wereadded tripotassium phosphate (269 mg, 1.01 mmol),(4-fluorophenyl)boronic acid (176 mg, 1.01 mmol) andchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(26 mg, 0.034 mmol). The mixture was stirred at 80° C. under nitrogenatmosphere for 2 hours. After completion, the mixture was concentratedunder reduced pressure. the residue was purified by silica gel columnchromatography (dichloromethane/methanol=100/1) to afford(2S,6R)-tert-butyl4-((S)-10-(3-chloro-4-fluorophenyl)-3-((methoxymethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(7) (150 mg, yield: 64%) as a yellow solid. MS (ESI) m/z 687.3 [M+H]⁺.

(S)-10-(3-chloro-4-fluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8)

To a cooled mixture of (2S,6R)-tert-butyl4-((S)-10-(3-chloro-4-fluorophenyl)-3-((methoxymethoxy)methyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(7) (150 mg, 0.22 mmol) in dichloromethane (2 mL) was addedtrifluoroacetic acid (2 mL) at 0° C. The reaction solution was stirredat room temperature for 1 hour. After completion, the mixture wasadjusted PH=7˜8 with sodium bicarbonate solution. After extraction andconcentration, the residue was purified by silica gel columnchromatography (dichloromethane/methanol=10/1) to afford(S)-10-(3-chloro-4-fluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8) (90 mg, yield: 70%) as a yellow solid. MS (ESI) m/z 587.2 [M+H]⁺.

(S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(3-chloro-4-fluorophenyl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(9)

To a mixture of(S)-10-(3-chloro-4-fluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(7) (90 mg, 0.15 mmol) and triethyl amine (45 mg, 0.45 mmol) indichloromethane (2 ml) was added acrylic anhydride (28 mg, 0.23 mmol) at0° C. The mixture was stirred at room temperature for 1 hour. Aftercompletion, the mixture was poured into ice-water (20 mL) and extractedwith dichloromethane (20 mL×3). Concentrated and the residue waspurified by preparative High Performance Liquid Chromatography (20% to95% acetonitrile in water) to afford(S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(3-chloro-4-fluorophenyl)-3-((methoxymethoxy)methyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(8) (20 mg, yield: 21%) as a white solid. MS (ESI) m/z 641.1 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.24-7.15 (m, 4H), 6.63-6.56 (m,1H), 6.39 (d, J=16.4 Hz, 1H), 5.80 (d, J=10.4 Hz, 1H), 5.46-5.45 (m,1H), 4.67-4.62 (m, 2H), 4.02-3.95 (m, 3H), 3.81-3.79 (m, 7H), 3.35-3.33(m, 4H), 3.01-2.98 (m, 1H).

Example 2016:(3S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-3-(ethoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one

(R)-4-(ethoxymethyl)-2,2-dimethyl-1,3-dioxolane (2)

To a mixture of (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (25 g,189.2 mmol) in dimethylformamide (350 mL) was added sodium hydride (16.8g, 492.0 mmol). The mixture was stirred at 0° C. to room temperature for0.5 hour. Consequently, iodoethane (37.0 g, 237.2 mmol) was added. Themixture was stirred at room temperature overnight. After completion, themixture was poured into saturated ammonium chloride solution (200 mL),washed with ethyl acetate (200 mL×3). The organic phase was washed withwater (100 mL) and dried over anhydrous sodium sulfate. After filtrationand concentration under reduce pressure, the title compound (2) wasobtained (19.9 g, 124.2 mmol, crude) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 4.32-4.23 (m, 1H), 4.06 (dd, J=8.4 Hz, 6.8 Hz,1H), 3.72 (dd, J=8.4 Hz, 6.4 Hz, 1H), 3.38-3.53 (m, 3H), 3.43 (dd,J=10.4 Hz, 5.6 Hz, 1H), 1.43 (s, 3H), 1.37 (s, 3H), 1.21 (t, 6.8 Hz,3H).

(S)-3-ethoxypropane-1,2-diol (3)

The mixture of (R)-4-(ethoxymethyl)-2,2-dimethyl-1,3-dioxolane (2) (19.9g, 124.2 mmol, crude) and hydrogen chloride (1200 mmol) intetrahydrofuran (100 mL) and water (100 mL) was stirred at roomtemperature overnight. The solvent was evaporated, and the residue waspurified by silica gel chromatography (dichloromethane/methanol=100/1 to30/1) to afford the title compound (3) (5.9 g, 49.1 mmol, 40% yield) asa yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 3.91-3.85 (m, 1H), 3.69 (dd, J=11.2 Hz, 3.6Hz, 1H), 3.60 (dd, J=11.6 Hz, 6.0 Hz, 1H), 3.58-3.43 (m, 5H), 3.19 (s,1H), 1.21 (t, 7.2 Hz, 3H).

(R)-3-ethoxy-2-hydroxypropyl 4-methylbenzenesulfonate (4)

To a mixture of (S)-3-ethoxypropane-1,2-diol (3) (5.9 g, 49.1 mmol) andtriethylamine (8.6 mL, 61.4 mmol) in dichloromethane (60 mL) was addedp-toluenesulfonyl chloride (5.9 g, 36.8 mmol) at 0° C. The mixture wasstirred at room temperature overnight. The solvent was evaporated, andthe residue was purified by silica gel chromatography(dichloromethane/methanol=200/1 to 50/1) to afford the title compound(4) (5.5 g, 20 mmol, 38% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.83-7.78 (m, 2H), 7.38-7.33 (m, 2H),4.17-3.92 (m, 3H), 3.52-3.39 (m, 4H), 2.50 (d, 5.6 Hz, 1H), 2.45 (s,3H), 1.15 (t, 7.2 Hz, 3H).

(R)-1-ethoxy-3-mercaptopropan-2-ol (5)

To a mixture of (R)-3-ethoxy-2-hydroxypropyl 4-methylbenzenesulfonate(4)(5.5 g, 20.0 mmol) in ethanol (60 mL) was added sodium hydrosulfide(2.8 g, 50.1 mmol). The mixture was stirred at 30° C. for 2 hours. Afterconcentration under reduce pressure, the residue was washed withdichloromethane. After filtration and concentration, the residue waspurified by silica gel chromatography (dichloromethane/methanol=200/1 to60/1) to give the title compound (5) (2.01 g, 14.76 mmol, crude) as ayellow oil.

(R)-7-chloro-8-((3-ethoxy-2-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(6)

The mixture of7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2.89 g,7.40 mmol), potassium carbonate (3.07 g, 22.2 mmol),4,5-Bis(diphenyl-phosphino)-9,9-dimethylxanthene (0.64 g, 1.11 mmol),(R)-1-ethoxy-3-mercaptopropan-2-ol (2.01 g, 14.76 mmol) andTris(dibenzylideneacetone) dipalladium (1.01 g, 1.11 mmol) in dioxane(40 mL) was stirred under nitrogen atmosphere at 55° C. overnight. Aftercompletion, the mixture was washed with dichloromethane and filtrated.After concentration, the residue was purified by silica gel column with(dichloromethane/methanol=200/1 to 30/1) to afford the product (6) (1.70g, 4.26 mmol, yield: 58%) as a yellow solid. LC-MS: [M−H], m/z=397.1.

(S)-10-chloro-3-(ethoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(7)

To a mixture of(R)-7-chloro-8-((3-ethoxy-2-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(6) (1.70 g, 4.26 mmol) and triphenylphosphine (2.23 g, 8.53 mmol) intetrahydrofuran (320 mL) was slowly added Diethyl azodicarboxylate (1.45g, 8.53 mmol) at 0° C. under nitrogen atmosphere. The mixture wasstirred at room temperature for 2 hour. dichloromethane (200 mL) wasadded. The organic phase was washed with water (200 mL×2), dried overanhydrous sodium sulfate. The mixture was concentrated, and the residuewas purified by flash chromatography column (C18, acetonitrile/water=20%to 95%) to afford the product (7) (1.10 g, 2.89 mmol, yield: 72%) as awhite solid. LC-MS: [M−H], m/z=378.9.

(2S,6R)-tert-butyl4-((S)-10-chloro-3-(ethoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(8)

To a solution of(S)-10-chloro-3-(ethoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione(7) (1.10 g, 2.89 mmol) in acetonitrile (110 mL) were added potassiumcarbonate (3.99 g, 28.89 mmol) and 4-methylbenzenesulfonic anhydride(2.83 g, 8.67 mmol). The mixture was stirred at room temperature for 7hours. The mixture was added (2S,6R)-tert-butyl2,6-dimethylpiperazine-1-carboxylate (2.48 g, 11.56 mmol) to the mixtureand then stirred at room temperature overnight. After completion, themixture was poured into ice-water (300 mL) and extracted with ethylacetate (200 mL×3). Concentrated and the residue was purified by flashchromatography column (C18, acetonitrile/water=20% to 95%) to afforddesired (8) product (1.45 g, yield: 87%) as a yellow solid. LC-MS: m/z577.5 [M+H]⁺;

(2S,6R)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-3-(ethoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(9)

Chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(27 mg, 0.04 mmol) was added to a mixture of (2S,6R)-tert-butyl4-((S)-10-chloro-3-(ethoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(200 mg, 0.35 mmol), (2,4-difluorophenyl)boronic acid (274 mg, 1.73mmol) and tripotassium phosphate (441 mg, 2.08 mmol) in 1,4-dioxane (5mL) and water (1 mL) at 85° C. under nitrogen atmosphere. The mixturewas stirred at 85° C. for 2 hours. The mixture was washed withdichloromethane and filtrated. After concentration, the residue waspurified by flash chromatography column (C18, acetonitrile/water=20% to95%) to afford the product (9) (197 mg, 0.30 mmol, yield: 86%) as awhite solid. LC-MS: m/z 655.6 [M+H]⁺.

(3S)-10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(ethoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(10)

To a solution of (2S,6R)-tert-butyl4-((3S)-10-(2,4-difluorophenyl)-3-(ethoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate(197 mg, 0.30 mmol) in dichloromethane (2 mL) was added Trifluoroaceticacid (2 mL) at 0° C. The mixture was stirred at room temperature for 1hour. The mixture was concentrated, and the residue was purified bysilica gel column (dichloromethane/methanol=100/1 to 20/1) to afford theproduct (10) (135 mg, 0.24 mmol, crude) as a yellow solid. LC-MS: m/z555.5 [M+H]⁺.

(3S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-3-(ethoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(11)

To a mixture of(3S)-10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(ethoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one(10) (135 mg, 0.24 mmol) and triethyl amine (74 mg, 0.73 mmol) indichloromethane (5 mL) was added Acrylic anhydride (31 mg, 0.24 mmol) at0° C. The mixture was stirred at room temperature for 2 hours. Afterconcentration, the residue was purified by prep-HPLC to afford theproduct (11) (37 mg, 0.06 mmol, 25% yield) as a white solid. LC-MS: m/z609.2 [M+H]+.

¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.23-7.13 (m, 1H), 7.08-6.92 (m,2H), 6.63 (dd, J=16.8 Hz, 6.0 Hz, 1H), 6.41 (dd, J=16.8 Hz, 1.6 Hz, 1H),5.78 (dd, J=10.8 Hz, 1.6 Hz, 1H), 5.51-5.38 (m, 1H), 5.00-4.40 (m, 2H),4.25-4.14 (m, 2H), 3.74-3.47 (m, 4H), 3.43-3.28 (m, 3H), 3.07-2.97 (m,1H), 1.63 (d, J=7.2 Hz, 3H), 1.48 (d, J=6.4 Hz, 3H), 1.18 (t, J=6.8 Hz,3H).

Examples 2034 and 2035:8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-((dimethylamino)methyl)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one

(2,2-dimethyl-1,3-dioxan-5-yl)methyl 4-methylbenzenesulfonate (2)

To a mixture of (2,2-dimethyl-1,3-dioxan-5-yl)methanol (10.5 g, 71.9mmol) in dichloromethane (200 mL) was added triethylamine (21.8 g, 215.7mmol) and tosyl chloride (20.5 g, 107.9 mmol) at 0° C. The mixture wasstirred at room temperature for 2 hours. After completion, the mixturewas concentrated and the residue was purified by silica gel column(dichloromethane/methanol=90/1) to afford(2,2-dimethyl-1,3-dioxan-5-yl)methyl 4-methylbenzenesulfonate (2) (22.2g, crude) as a white solid. MS (ESI) m/z 301 [M+H]⁺.

(2,2-dimethyl-1,3-dioxan-5-yl)methanethiol (3)

To a solution of (2,2-dimethyl-1,3-dioxan-5-yl)methyl4-methylbenzenesulfonate (12.0 g, crude) in N,N-dimethylformamide (100mL) was added sodium hydrosulfide (9.6 g, 120.0 mmol) at roomtemperature. The mixture was stirred at room temperature for 2 hours.After completion, the mixture was extracted with ethyl acetate and theorganic phase was concentrated under reduce pressure. The residue waspurified by silica gel column (dichloromethane/methanol=90/1) to afford(2,2-dimethyl-1,3-dioxan-5-yl)methanethiol (3) (3.4 g, yield: 52%) as ayellow oil. MS (ESI) m/z 163.0 [M+H]⁺.

7-chloro-8-(((2,2-dimethyl-1,3-dioxan-5-yl)methyl)thio)-4-hydroxy-6-(trifluoromethyl)quinazolin-2(1H)-one(4)

To a mixture of7-chloro-4-hydroxy-8-iodo-6-(trifluoromethyl)quinazolin-2(1H)-one (5.3g, 13.6 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.6g, 2.7 mmol) in 1,4-dioxane (600 mL) was addedtris(dibenzylideneacetone)dipalladium (1.3 g, 1.3 mmol), potassiumcarbonate (5.6 g, 40.7 mmol) and(2,2-dimethyl-1,3-dioxan-5-yl)methanethiol (2.9 g, 17.9 mmol) at roomtemperature. The mixture was stirred at 60° C. overnight. Afterfiltration and concentration, the residue was purified by silica gelchromatography (dichloromethane/methanol=1/10) to afford7-chloro-8-(((2,2-dimethyl-1,3-dioxan-5-yl)methyl)thio)-4-hydroxy-6-(trifluoromethyl)quinazolin-2(1H)-one(4) (4.21 g, 9.9 mmol) as a white solid. MS (ESI) m/z 425.0 [M+H]⁺.

7-chloro-4-hydroxy-8-((3-hydroxy-2-(hydroxymethyl)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(5)

The mixture of7-chloro-8-(((2,2-dimethyl-1,3-dioxan-5-yl)methyl)thio)-4-hydroxy-6-(trifluoromethyl)quinazolin-2(1H)-one(4.2 g, 9.9 mmol) in acetonitrile was added hydrochloric acid (20 mL,5N). The mixture was stirred at room temperature for 1 hour. Aftercompletion, the mixture was filtered. The filter cake was dried underreduce pressure to afford7-chloro-4-hydroxy-8-((3-hydroxy-2-(hydroxymethyl)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(5) (4.17 g, 10.8 mmol, crude) as a white solid. MS (ESI) m/z 385.0[M+H]⁺.

11-chloro-8-hydroxy-3-(hydroxymethyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(6)

To a mixture of7-chloro-4-hydroxy-8-((3-hydroxy-2-(hydroxymethyl)propyl)thio)-6-(trifluoromethyl)quinazolin-2(1H)-one(5) (4.0 g, 10.4 mmol) and triphenylphosphine (4.09 g, 15.6 mmol) intetrahydrofuran and N,N-dimethylformamide was added diethylazodicarboxylate (2.72 g, 15.6 mmol) at 0° C. under nitrogen atmosphere.The mixture was stirred at room temperature for 1 hour. Aftercompletion, the mixture was concentrated and the residue was purified byflash chromatography column (C18, acetonitrile/water=20% to 95%) toafford11-chloro-8-hydroxy-3-(hydroxymethyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(6) (2.8 g, 7.65 mmol, yield: 73%) as a white solid. MS (ESI) m/z 367.3[M+H]⁺.

3-(((tert-butyldimethylsilyl)oxy)methyl)-11-chloro-8-hydroxy-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(7)

To a mixture of11-chloro-8-hydroxy-3-(hydroxymethyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(2.8 g, 7.65 mmol) and imidazole (2.08 g, 30.6 mmol) inN,N-dimethylformamide (30 mL) was added tert-butyldimethylsilyl chloride(2.31 g, 15.3 mmol) at 25° C. The mixture was stirred at 25° C. for 1hour. After completion, the mixture was extracted with ethyl acetate.Concentrated and the residue was purified by silica gel column(petroleum ether/ethyl acetate=7/1) to give the title product (7) (3.7g, crude) as yellow solid. MS (ESI) m/z 481.2 [M+H]⁺.

(2S,6R)-tert-butyl4-(3-(((tert-butyldimethylsilyl)oxy)methyl)-11-chloro-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(8)

To a solution of3-(((tert-butyldimethylsilyl)oxy)methyl)-11-chloro-8-hydroxy-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(7) (3.7 g, 7.7 mmol) in acetonitrile were added potassium carbonate(5.3 g, 38.5 mmol) and 2,4,6-triisopropylbenzenesulfonyl chloride (3.5g, 11.55 mmol). The mixture was stirred at 25° C. under nitrogenatmosphere for 5 hours. Above mixture was added (2S,6R)-tert-butyl2,6-dimethylpiperazine-1-carboxylate (2.64 g, 12.3 mmol) at roomtemperature and stirred at 25° C. under nitrogen atmosphere overnight.After completion, the mixture was filtered. The filtration wasconcentrated under reduce pressure and extracted with ethyl acetate.After concentration, the residue was purified by silica gel column(dichloromethane/methanol=80/1) to afford the title product (8) (4.3 g,6.36 mmol, yield: 82%) as a yellow solid. (ESI) m/z 677.2 [M+H]⁺.

(2S,6R)-tert-butyl4-(3-(((tert-butyldimethylsilyl)oxy)methyl)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(9)

To a mixture of (2S,6R)-tert-butyl4-(3-(((tert-butyldimethylsilyl)oxy)methyl)-11-chloro-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(8) (1.1 g, 1.62 mmol) in 1,4-dioxane and water was added[2′-(Amino)[1,1′-biphenyl]-2-yl][[2′,6′-bis(1-methylethoxy)[1,1′-biphenyl]-2-yl]dicyclohexylphosphine]chloropalladium(253 mg, 0.325 mmol), potassium phosphate trihydrate (2.16 g, 8.13 mmol)and (4-fluorophenyl)boronic acid (1.14 g, 8.13 mmol) at 25° C. Themixture was stirred at 85° C. for 2 hours. After completion, the mixturewas concentrated and the residue was purified by silica gel columnchromatography (dichloromethane/ethyl acetate=80/1) to afford(2S,6R)-tert-butyl4-(3-(((tert-butyldimethylsilyl)oxy)methyl)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(9) (1.5 g, crude) as a yellow solid. (ESI) m/z 737.2 [M+H]⁺.

(2S,6R)-tert-butyl4-(11-(4-fluorophenyl)-3-(hydroxymethyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(10)

To a mixture of (2S,6R)-tert-butyl4-(3-(((tert-butyldimethylsilyl)oxy)methyl)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(9) (1.42 g, 1.93 mmol) in dichloromethane (10 mL) was addedtetrabutylammonium fluoride (20 mL, 1N in tetrahydrofuran) at 25° C. Themixture was stirred at 25° C. for 1 hour. After completion, the mixturewas extracted with dichloromethane. After concentration, the residue waspurified by silica gel column chromatography(dichloromethane/methanol=83/1) to afford (2S,6R)-tert-butyl4-(11-(4-fluorophenyl)-3-(hydroxymethyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(10) (1.0 g, 0.013 mmol, yield: 83%) as yellow solid. MS (ESI) m/z 623.2[M+H]⁺.

(2S,6R)-tert-butyl4-(3-((dimethylamino)methyl)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(11)

To a mixture of (2S,6R)-tert-butyl4-(11-(4-fluorophenyl)-3-(hydroxymethyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(10) (500 mg, 0.8 mmol) in dichloromethane (4 mL) was added Dess-martinreagent (511 mg, 1.2 mmol) at 25° C. The mixture was stirred at 25° C.for 1 hour. After completion, a solution of dimethylamine (0.6 mL, 2N intetrahydrofuran) and sodium triacetoxyborohydride (256 mg, 1.2 mmol) indichloromethane (4 mL) was added to above mixture at 25° C. The mixturewas stirred at 25° C. for 1 hour. After completion, the mixture wasconcentrated and the residue was purified by silica gel columnchromatography (dichloromethane/methanol=21/1) to afford(2S,6R)-tert-butyl4-(3-((dimethylamino)methyl)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(11) (468 mg, 0.72 mmol, yield: 89%) as yellow solid. MS (ESI) m/z 650.2[M+H]⁺.

3-((dimethylamino)methyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(12)

To a mixture of (2S,6R)-tert-butyl4-(3-((dimethylamino)methyl)-11-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(11) (468 mg, 0.72 mmol) in dichloromethane (6 mL) was addedtrifluoroacetic acid (3 mL) at 25° C. The mixture was stirred at 25° C.for 1 hour. After completion, the mixture was concentrated and adjustedPH to 8 with ammonia in methanol at 0° C. The mixture was concentratedand purified by silica gel column chromatography(dichloromethane/methanol=30/1) to afford3-((dimethylamino)methyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(12) (264 mg, 0.48 mmol, yield: 66%) as yellow solid. MS (ESI) m/z 550.2[M+H]⁺.

8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-((dimethylamino)methyl)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(13)

To a mixture of3-((dimethylamino)methyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(12) (244 mg, 0.44 mmol) in dichloromethane (4 mL) was addedtriethylamine (135 mg, 1.32 mmol) and acrylic anhydride (84 mg, 0.66mmol) at 5° C. The mixture was stirred at 25° C. for 1 hour. Aftercompletion, the mixture was added methanol at 25° C. and concentrated.The mixture was purified by preparative high performance liquidchromatography (20% to 95% acetonitrile in water) to afford8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-((dimethylamino)methyl)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(13) (124 mg, 0.2 mmol, yield: 46%) as a pale yellow powder.

MS (ESI) m/z 603.6 [M+H]⁺. ¹H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H),7.22-7.15 (m, 4H), 6.66-6.59 (m, 1H), 6.41 (d, J=16.4 Hz, 1H), 5.77 (d,J=10.4 Hz, 1H), 4.84-4.44 (m, 3H), 4.27-3.99 (m, 3H), 3.37-3.19 (m, 3H),3.09-2.97 (m, 1H), 2.68-2.44 (m, 1H), 2.30-2.21 (m, 8H), 1.59-1.51 (m,6H).

Examples 2038 and 2039:8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(((S)-3-fluoropyrrolidin-1-yl)methyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one

(2S,6R)-tert-butyl4-(11-(4-fluorophenyl)-3-(((S)-3-fluoropyrrolidin-1-yl)methyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(14)

To a mixture of (2S,6R)-tert-butyl4-(11-(4-fluorophenyl)-3-(hydroxymethyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(400 mg, 0.64 mmol) in dichloromethane (6 mL) was added Dess-martin (409mg, 0.96 mmol) at 25° C. The mixture was stirred at 25° C. for 1 hour.After completion, a solution of (S)-3-fluoropyrrolidine hydrochloride(121 mg, 0.96 mmol) and sodium triacetoxyborohydride (205 mg, 0.96 mmol)in dichloromethane (4 mL) was added to above mixture at 25° C. Themixture was stirred at 25° C. for 1 hour. After completion, the mixturewas concentrated and the residue was purified by silica gel columnchromatography (dichloromethane/methanol=21/1) to afford(2S,6R)-tert-butyl4-(11-(4-fluorophenyl)-3-(((S)-3-fluoropyrrolidin-1-yl)methyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(14) (400 mg, 0.58 mmol, yield: 89%) as yellow solid. MS (ESI) m/z 694.2[M+H]⁺.

8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(((S)-3-fluoropyrrolidin-1-yl)methyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(15)

To a mixture of (2S,6R)-tert-butyl4-(11-(4-fluorophenyl)-3-(((S)-3-fluoropyrrolidin-1-yl)methyl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(14) (400 mg, 0.58 mmol) in dichloromethane (6 mL) was addedtrifluoroacetic acid (3 mL) at 25° C. The mixture was stirred at 25° C.for 1 hour. After completion, the mixture was concentrated and adjustedPH to 8 with ammonia in methanol at 0° C. The mixture was concentratedand purified by silica gel column chromatography(dichloromethane/methanol=30/1) to afford8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(((S)-3-fluoropyrrolidin-1-yl)methyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(15) (216 mg, 0.36 mmol, yield: 63%) as yellow solid. MS (ESI) m/z 594.2[M+H]⁺.

8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(((S)-3-fluoropyrrolidin-1-yl)methyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(16)

To a mixture of8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(((S)-3-fluoropyrrolidin-1-yl)methyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(15) (216 mg, 0.36 mmol) in dichloromethane (4 mL) was addedtriethylamine (110 mg, 1.09 mmol) and acrylic anhydride (69 mg, 0.55mmol) at 5° C. The mixture was stirred at 25° C. for 1 hour. Aftercompletion, the mixture was added methanol at 25° C. and concentrated.The mixture was purified by preparative high performance liquidchromatography (20% to 95% acetonitrile in water) to afford8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(((S)-3-fluoropyrrolidin-1-yl)methyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one(16) (119 mg, 0.18 mmol, yield: 50%) as a pale yellow powder. MS (ESI)m/z 648.6 [M+H]⁺. ¹H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.21-7.15 (m,4H), 6.66-6.59 (m, 1H), 6.41 (d, J=16.4 Hz, 1H), 5.78 (d, J=10.8 Hz,1H), 5.18-5.04 (m, 1H), 4.80-4.41 (m, 3H), 4.26-4.05 (m, 3H), 3.37-3.22(m, 3H), 3.13-3.02 (m, 1H), 2.86-2.72 (m, 3H), 2.64-2.53 (m, 2H),2.43-2.26 (m, 2H), 2.16-1.91 (m, 2H), 1.59-1.51 (m, 6H).

Example 2084:(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(4-fluorophenoxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

(R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (2)

To a mixture of (S)-2-((benzyloxy)methyl)oxirane (25 g, 152.4 mmol) andpotassium fluoride (17.7 g, 304.8 mmol) in methanal (250 mL) was addedtriphenylmethanethiol (42 g, 152.4 mmol). The mixture was stirred atroom temperature for 18 hours. After completion, the mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column with petroleum ether/ethyl acetate=5/1 to afford(R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (2) (60 g, 90% yield) as acolorless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.44-7.38 (m, 6H), 7.35-7.18 (m, 14H), 4.46(s, 2H), 3.58-3.48 (m, 1H), 3.37-3.26 (m, 2H), 2.45-2.35 (m, 2H).

(S)-(3-(benzyloxy)-2-(4-fluorophenoxy)propyl)(trityl)sulfane (3)

To a mixture of 4-fluorophenol (5.1 g, 45.45 mmol) andtriphenylphosphine (14.3 g, 54.54 mmol) in tetrahydrofuran (400 mL) wasadded diethyl azodicarboxylate (9.5 g, 54.54 mmol) at 0° C. undernitrogen atmosphere. The mixture was stirred at room temperature for 10min, then was added (R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (20 g,45.45 mmol). The mixture was stirred for 2 hours. After completion, themixture was poured into ice-water (300 mL) and extracted with ethylacetate (150 mL×3). After concentration, the residue was purified bysilica gel column with petroleum ether/ethyl acetate=50/1 to afford toafford crude(S)-(3-(benzyloxy)-2-(4-fluorophenoxy)propyl)(trityl)sulfane (3) (17.8g, crude) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.41 (m, 6H),7.37-7.17 (m, 14H), 6.89-6.84 (m, 2H), 6.66-6.62 (m, 2H), 4.48 (s, 2H),3.97-3.94 (m, 1H), 3.53-3.49 (m, 2H), 2.66-2.53 (m, 2H).

(S)-3-(benzyloxy)-2-(4-fluorophenoxy)propane-1-thiol (4)

To a mixture of(S)-(3-(benzyloxy)-2-(4-fluorophenoxy)propyl)(trityl)sulfane (17.8 g,33.3 mmol) and triethylsilane (9.7 g, 83.3 mmol) in dichloromethane (100mL) was added trifluoroacetic acid (38 g, 333 mmol). The mixture wasstirred at room temperature for 2 hours. After completion, the mixturewas concentrated and adjusted pH=7˜8 at 0° C. After concentration, theresidue was purified by silica gel column with petroleum ether/ethylacetate=15/1 to afford(S)-3-(benzyloxy)-2-(4-fluorophenoxy)propane-1-thiol (4) (5 g, 51%yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.21 (m, 4H),7.05-7.04 (m, 1H), 6.91-6.81 (m, 4H), 4.49 (d, J=4.8 Hz, 2H), 4.31-4.28(m, 1H), 3.65-3.60 (m, 2H), 2.86-2.71 (m, 2H), 1.46 (t, J=9.2 Hz, 1H).

(S)-8-((3-(benzyloxy)-2-(4-fluorophenoxy)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol(5)

To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4-diol(2.67 g, 6.85 mmol) in 1,4-dioxane (100 mL) was added potassiumcarbonate (2.36 g, 17.1 mmol),(S)-3-(benzyloxy)-2-(4-fluorophenoxy)propane-1-thiol (5 g, 17.1 mmol),4,5-Bis(diphenyl-phosphino)-9,9-dimethylxanthene (594 mg, 1.03 mmol) andTris(dibenzylideneacetone) dipalladium (630 mg, 0.685 mmol). The mixturewas stirred at 60° C. under nitrogen atmosphere for 18 hours. Aftercompletion, the mixture was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography(dichloromethane/ethyl acetate=3/1) to afford(S)-8-((3-(benzyloxy)-2-(4-fluorophenoxy)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol(5) (2.4 g, yield: 63%) as pale yellow solid. MS (ESI) m/z 553.3 [M−H]⁺.

(S)-7-chloro-8-((2-(4-fluorophenoxy)-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol(6)

A solution of(S)-8-((3-(benzyloxy)-2-(4-fluorophenoxy)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol(2.4 g, 4.33 mmol) in trifluoroacetic acid (12 mL) was stirred at 80° C.for 18 hrs. After completion, the mixture was concentrated and adjustedpH=7˜8 at 0° C. After concentration, the residue was purified by silicagel column with dichloromethane/ethyl acetate=1/2 to afford(S)-7-chloro-8-((2-(4-fluorophenoxy)-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol(6) (1.8 g, yield: 90%) as a yellow solid. MS (ESI): m/z 463 [M−H]⁺.

(S)-11-chloro-3-(4-fluorophenoxy)-8-hydroxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(7)

To a mixture of(S)-7-chloro-8-((2-(4-fluorophenoxy)-3-hydroxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol(1.7 g, 3.66 mmol) and triphenylphosphine (2.87 g, 10.95 mmol) intetrahydrofuran (100 mL) was added diethyl azodicarboxylate (1.91 g,10.95 mmol) at 0° C. The mixture was stirred at 0° C. for 45 min. Aftercompletion, the mixture was poured into ice-water (100 mL) and extractedwith ethyl acetate (100 mL×3). Concentrated and the residue was purifiedby C18 with 30-95% acetonitrile in water to afford(S)-11-chloro-3-(4-fluorophenoxy)-8-hydroxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(7) (1.27 g, 78% yield) as a yellow solid. MS (ESI) m/z 445.2 [M−H]⁺.

tert-butyl(2S,6R)-4-((S)-11-chloro-3-(4-fluorophenoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(8)

To a mixture of(S)-11-chloro-3-(4-fluorophenoxy)-8-hydroxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(7) (1.24 g, 2.78 mmol) and potassium carbonate (3.84 g, 27.8 mmol) inacetonitrile (50 mL) was added 4-methylbenzenesulfonic anhydride (1.81g, 5.55 mmol). The mixture was stirred at 35° C. for 4 hours. Aftercompletion, (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate(1.78 g, 8.32 mmol) was added into the reaction solution. The reactionmixture was stirred at 35° C. for 1 hour. After completion, the mixturewas poured into ice-water (200 mL) and extracted with ethyl acetate (100mL×3). Concentrated and the residue was purified by C18 column with20-95% acetonitrile in water to afford tert-butyl(2S,6R)-4-((S)-11-chloro-3-(4-fluorophenoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(8) (930 mg, yield: 52%) as a pale yellow solid. MS (ESI) m/z 643.4[M+H]⁺.

(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(4-fluorophenoxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(9)

To a solution of tert-butyl(2S,6R)-4-((S)-11-chloro-3-(4-fluorophenoxy)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate(8) (200 mg, 0.31 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) wasadded tripotassium phosphate (206 mg, 0.775 mmol),(4-fluorophenyl)boronic acid (131 mg, 0.93 mmol), andChloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(36 mg, 0.046 mmol). The mixture was stirred at 80° C. under nitrogenatmosphere for 1 hour. After completion, the mixture was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography (dichloromethane/methanol=60/1) to afford(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(4-fluorophenoxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(9) (240 mg, crude) as a yellow solid. MS (ESI) m/z 703.6 [M+H]⁺.

(S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(4-fluorophenoxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(10)

To a mixture of(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(4-fluorophenoxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(9) (240 mg, crude) in dichloromethane (2 mL) was added trifluoroaceticacid (2 mL) at 0° C. The reaction solution was stirred at roomtemperature for 1 hour. After completion, the mixture was concentratedand the residue was purified by silica gel column chromatography(dichloromethane/methanol=15/1) to afford(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(4-fluorophenoxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(10) (135 mg, yield: 66%) as a pale yellow solid. MS (ESI) m/z 603.2[M+H]⁺.

(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(4-fluorophenoxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(11)

To a mixture of(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(4-fluorophenoxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(10) (135 mg, 0.224 mmol) and triethyl amine (45 mg, 0.448 mmol) indichloromethane (3 ml) was added acrylic anhydride (42 mg, 0.336 mmol)at 0° C. The mixture was stirred at 0° C. for 1 hour. After completion,the mixture was poured into ice-water (30 mL) and extracted withdichloromethane (30 mL×3). Concentrated and the residue was purified bypreparative High Performance Liquid Chromatography (20% to 95%acetonitrile in water) to afford(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(4-fluorophenoxy)-11-(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one(11) (50 mg, yield: 34%) as a white solid. MS (ESI) m/z 657.2 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 7.26-7.24 (m, 1H), 7.20-7.16 (m,3H), 7.00-6.93 (m, 4H), 6.66-6.60 (m, 1H), 6.42 (dd, J=16.4 Hz, 1.6 Hz,1H), 5.78 (dd, J=10.4 Hz, 2.0 Hz, 1H), 4.96-4.60 (m, 5H), 4.18 (d,J=13.2 Hz, 2H), 3.43-3.35 (m, 3H), 3.17-3.13 (m, 1H), 1.55 (d, J=6.8 Hz,3H), 1.53 (d, J=6.4 Hz, 3H).

Example 2010 and 2011:(3S,10S)-7-((3S,5R)-4-(Acryloyl-d₃)-3,5-dimethylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(P1) and(3S,10R)-7-((3S,5R)-4-(Acryloyl-d₃)-3,5-dimethylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one(P2)

Compound 1 (190 mg, 0.28 mmol, 1 equiv) was dissolved in anhydrousCH₂Cl₂ (7 mL) in a 20 dr vial followed by the addition of CF₃COOH (3 mL)at room temperature and capped. After 15 min, the reaction wasdetermined to be complete by LC-MS and the solvent was removed by rotaryevaporation. Acrylic acid-d₄ (43 mg, 0.56 mmol, 2.0 equiv) in a 25 mLround-bottom flask under nitrogen was dissolved in anhydrous CH₂Cl₂ (12mL). DIPEA (98 μL, 0.56 mmol, 2.0 equiv followed by HATU (138 mg, 0.364mmol, 1.3 equiv) were added. Next, the deprotected amine dissolved inDMF (2 mL) was added and the resulting reaction mixture was stirred atroom temperature. After 21 h, the solvent was removed by rotaryevaporation. The mixture was transferred to a separatory funnel withEtOAc (200 mL) and washed with H₂O (30 mL, 3×). The organic layer wasdried over Na₂SO₄ and the solvent was removed by rotary evaporation. Thecrude material was dissolved in MeOH, filtered with a 0.45 μM PTFE plug,and purified by preparative RP-HPLC (Luna 5 μM C18(2) 100 Å, 100×30 mm,5-95% MeCN+0.1% (v/v) HCOOH and H₂O+0.1% (v/v) HCOOH). The productfractions were collected, and the solvent was removed by rotaryevaporation, followed by lyophilization (−91 to −71° C.; <0.01 mbar) indeionized water to afford P1 and P2 (41 mg, 23%) as a white solid. Theatropisomers were separated by chiral preparative HPLC on a CHIRALPAK®AD-H column to afford P1 (10.1 mg, 6% yield) and P2 (18 mg, 10% yield)as white solids.

P1: ¹H NMR (400 MHz, MeOH-d₄) δ 8.15 (s, 1H), 7.48 (t, J=7.6 Hz, 1H),7.38 (t, J=9.1 Hz, 1H), 5.42-5.34 (m, 1H), 4.83-4.56 (br s, 2H),4.41-4.21 (m, 2H), 3.73-3.40 (m, 5H), 3.39 (s, 3H), 3.17 (dd, J=13.6,3.0 Hz, 1H), 1.56 (d, J=6.9 Hz, 3H), 1.42 (d, J=6.9 Hz, 3H); LRMS-ESI(m/z) [M+H]⁺ calculated for C₂₈H₂₄D₃ClF₅N₄O₃S 632.16, found 632.2.

P2: ¹H NMR (400 MHz, MeOH-d₄) δ 8.15 (s, 1H), 7.53 (t, J=7.6 Hz, 1H),7.37 (t, J=9.1 Hz, 1H), 5.41-5.31 (m, 1H), 4.83-4.54 (br s, 2H),4.39-4.29 (m, 2H), 3.74 (t, J=9.2 Hz, 1H), 3.62 (dd, J=9.2, 4.8 Hz, 1H),3.49 (dd, J=13.5, 4.7 Hz, 1H), 3.45-3.37 (m, 2H), 3.40 (s, 3H), 3.15(dd, J=13.7, 3.0 Hz, 1H), 1.57 (d, J=7.0 Hz, 3H), 1.42 (d, J=7.0 Hz,3H); LRMS-ESI (m/z) [M+H]⁺ calculated for C₂₈H₂₄D₃ClF₅N₄O₃S 632.16,found 632.2.

Example 2082:8′-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-11′-(5-chloro-2,4-difluorophenyl)-3,3-difluoro-10′-(trifluoromethyl)-2′H,4′H,6′H-spiro[cyclobutane-1,3′-[1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one

The title compound was synthesized through the route shown above usingsimilar procedures as described in other examples.

¹H NMR (400 MHz, MeOH-d₄) δ 7.96 (s, 1H), 7.61-7.41 (m, 1H), 7.34 (td,J=9.2, 3.7 Hz, 1H), 6.92-6.71 (m, 1H), 6.37-6.21 (m, 1H), 5.81 (ddd,J=9.9, 7.2, 1.9 Hz, 1H), 4.87-4.38 (m, 4H), 4.37-3.33 (m, 10H),2.60-2.37 (m, 2H), 1.59-1.20 (m, 6H); LRMS-ESI (m/z) [M+H]⁺ calculatedfor C₃₀H₂₇ClF₇N₄O₂S 675.14, found 675.2.

TABLE 12 Summary of Compounds 2000 to 2109 Ex.# Structure Name ¹H NMRMS + 1 2001

(S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-10-(4-fluorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one ¹H NMR (400 MHz, CDCl₃) δ8.06 (s, 1H), 7.21-7.15 (m, 4H), 6.67-6.59 (m, 1H), 6.44- 6.37 (m, 1H),5.79-5.76 (m, 1H), 5.47-5.52 (m, 1H), 4.76- 4.55 (m, 2H), 4.24-4.16 (m,2H), 3.71-3.61 (m, 2H), 3.40- 3.30 (m, 6H), 2.99-2.91 (m, 1H), 1.63-1.61577.3 (m, 3H), 21.48- 1.46 (m, 3H). 2001

(S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-10-(3-chloro-4-fluorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one ¹H NMR (400 MHz, CDCl₃) δ8.05 (s, 1H), 7.30-7.28 (m, 1H), 7.25-7.23 (m, 1H), 7.14- 7.10 (m, 1H),6.66-6.59 (m, 1H), 6.43-6.38 (m, 1H), 5.79- 5.76 (m, 1H), 5.45-5.42 (m,1H), 4.66-4.55 (m, 1H), 4.21- 4.15 (m, 2H), 3.70-3.61 (m, 2H), 3.41-3.30611.2 (m, 6H), 2.99- 2.94 (m, 1H), 1.62-1.60 (m, 4H), 1.48-1.46 (m, 3H).2002

(3S,10S)-7-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1- yl)-10-(2,4-difluorophenyl)-3- ((methoxymethoxy) methyl)-9- (trifluoromethyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one ¹H NMR (400 MHz, CDCl₃) δ8.07 (s, 1H), 7.21-7.15 (m, 1H), 7.06-7.01 (m, 1H), 6.98- 6.93 (m, 1H),6.66-6.59 (m, 1H), 6.42 (dd, J = 1.6 Hz, 16.8 Hz, 1H), 5.78 (dd, J = 1.2Hz, 10.4 Hz, 1H), 5.51-5.49 (m, 1H), 4.67-4.62 (m, 4H), 4.22- 625.2 4.19(m, 2H), 3.82-3.74 (m, 2H), 3.40-3.3 (m, 6H), 3.07- 3.03 (m, 1H), 1.61(d, J = 6.8 Hz, 3H), 1.48 (d, J = 6.8 Hz, 3H). 2003

(3S,10S)-7-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1- yl)-10-(2,4-difluorophenyl)-3- ((methoxymethoxy) methyl)-9- (trifluoromethyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one ¹H NMR (400 MHz, CDCl₃) δ8.07 (s, 1H), 7.20-7.15 (m, 1H), 7.04-6.94 (m, 2H), 6.66- 6.59 (m, 1H),6.42 (dd, J = 1.2 Hz, 16.4 Hz, 1H), 5.78 (dd, J = 1.2 Hz, 10.0 Hz, 1H),5.48- 5.45 (m, 1H), 4.67-4.62 (m, 4H), 4.21-4.18 (m, 2H), 3.80- 3.78 (m,2H), 625.2 3.39-3.30 (m, 6H), 3.09-3.05 (m, 1H), 1.61 (d, J = 6.8 Hz,3H), 1.48 (d, J = 6.8 Hz, 3H). 2004

(S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-10-(3-chloro-4-fluorophenyl)-3- ((methoxymethoxy) methyl)-9- (trifluoromethyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one ¹H NMR (400 MHz, CDCl₃) δ8.05 (s, 1H), 7.32-7.23 (m, 2H), 7.13-7.10 (m, 1H), 6.65- 6.59 (m, 1H),6.43 (dd, J = 12.8 Hz, 2 Hz, 1H), 5.79 (dd, J = 8.4 Hz, 1.6 Hz, 1H),5.48- 5.46 (m, 1H), 4.68-4.62 (m, 3H), 4.20-4.17 (m, 2H), 3.83- 3.77 (m,2H), 641.1 3.39-3.30 (m, 6H), 3.03-2.98 (m, 1H), 1.62- 1.60 (m, 4H),1.48-1.46 (m, 3H). 2005

(S)-7-((3S,5R)-4- (Acryloyl-d₃)-3,5- dimethylpiperazin-1- yl)-10-(4-fluorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ8.13 (s, 1H), 7.34-7.19 (m, 4H), 5.38- 5.30 (m, 1H), 4.81-4.57 (br s,2H), 4.39-4.22 (m, 2H), 3.73 (t, J = 9.2 Hz, 1H), 3.60 (dd, J = 9.2, 4.8Hz, 1H), 3.49 (dd, J = 13.5, 4.7 Hz, 1H), 3.39 (s, 3H), 3.45-3.33 (m,2H), 3.09 (dd, J = 13.6, 580.3 2.9 Hz, 1H), 1.57 (d, J = 7.0 Hz, 3H),1.42 (d, J = 7.0 Hz, 3H). 2006

(3S,10S)-7-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-chloro-2,4- difluorophenyl)-3- ((methoxymethoxy) methyl)-9-(trifluoromethyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one 1HNMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.29-7.26 (m, 1H), 7.08-7.04 (m,1H), 6.65- 6.59 (m, 1H), 6.43 (dd, J = 16.8 Hz, 2 Hz, 1H), 5.79 (dd, J =10 Hz, 1.6 Hz, 1H), 5.52-5.48 (m, 1H), 4.68- 4.62 (m, 3H), 4.21-4.17 (m,2H), 3.81-3.76 (m, 2H), 3.42- 659.3 3.30 (m, 6H), 3.08-3.04 (m, 1H),1.62-1.57 (m, 4H), 1.47 (d, J = 6.8 Hz, 3H). 2007

(3S,10S)-7-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-chloro-2,4- difluorophenyl)-3- ((methoxymethoxy) methyl)-9-(trifluoromethyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one MHz,CDCl₃) δ 8.06 (s, 1H), 7.29-7.26 (m, 1H), 7.10-7.05 (m, 1H), 6.65- 6.58(m, 1H), 6.43 (dd, J = 16.4 Hz, 2 Hz, 1H), 5.79 (dd, J = 10.8 Hz, 2 Hz,1H), 5.50-5.46 (m, 1H), 4.68- 4.63 (m, 3H), 4.21-4.17 (m, 2H), 3.80-3.78(m, 2H), 3.42- 3.31 (m, 6H), 659.3 3.09-3.05 (m, 1H), 1.61-1.60 (m, 4H),1.48 (d, J = 6.8 Hz, 3H). 2008

(S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-10-(2,6-difluorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one ¹H NMR (400 MHz, CDCl₃) δ8.10 (s, 1H), 7.55-7.45 (m, 1H), 7.05 (t, J = 8.0 Hz, 2H), 6.63 (dd, J =16.8 Hz, 10.4 Hz, 1H), 6.41 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.78 (dd, J =10.4 Hz, 2.0 Hz, 1H), 5.50-5.45 (m, 1H), 4.70- 4.61 (m, 2H), 4.29-4.11(m, 595.2 2H), 3.70-3.61 (m, 2H), 3.40 (s, 3H), 3.38-3.30 (m, 3H), 3.07(dd, J = 13.5, 2.7 Hz, 1H), 1.63 (d, J = 7.2 Hz, 3H), 1.48 (d, J = 7.2Hz, 3H). 2009

(S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-3-(methoxymethyl)-9- (trifluoromethyl)-10- (2,4,6- trifluorophenyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one ¹H NMR (400 MHz, CDCl₃) δ8.09 (s, 1H), 6.82 (t, J = 7.2 Hz, 2H), 6.62 (dd, J = 10.8 Hz, J = 16.8Hz, 1H), 6.40 (dd, J = 1.6 Hz, J = 16.4 Hz, 1H), 5.77 (dd, J = 1.6 Hz, J= 10.4 Hz, 1H), 5.50-5.45 (m, 1H), 4.85- 4.52 (m, 2H), 4.22-4.16 (m,2H), 3.67-3.60 (m, 2H), 3.40 (s, 3H), 3.37-3.30 (m, 3H), 3.07 (dd, J =2.8 Hz, J = 13.2 Hz, 1H), 1.62 (d, J = 6.8 Hz, 3H), 1.47 (d, J = 7.2 Hz,3H). 2010

(3S,10S)-7-((3S,5R)- 4-(Acryloyl-d₃)-3,5- dimethylpiperazin-1-yl)-10-(5-chloro-2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ 8.15 (s, 1H), 7.48 (t,J = 7.6 Hz, 1H), 7.38 (t, J = 9.1 Hz, 1H), 5.42- 5.34 (m, 1H), 4.83-4.56(br s, 2H), 4.41-4.21 (m, 2H), 3.73- 3.40 (m, 5H), 3.39 (s, 3H), 3.17(dd, J = 13.6, 3.0 Hz, 1H), 1.56 (d, J = 6.9 Hz, 3H), 1.42 (d, J = 6.9Hz, 3H); 632.2 2011

(3S,10R)-7-((3S,5R)- 4-(Acryloyl-d₃)-3,5- dimethylpiperazin-1-yl)-10-(5-chloro-2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ 8.15 (s, 1H), 7.53 (t,J = 7.6 Hz, 1H), 7.37 (t, J = 9.1 Hz, 1H), 5.41- 5.31 (m, 1H), 4.83-4.54(br s, 2H), 4.39-4.29 (m, 2H), 3.74 (t, J = 9.2 Hz, 1H), 3.62 (dd, J =9.2, 4.8 Hz, 1H), 3.49 (dd, J = 13.5, 4.7 Hz, 1H), 3.45-3.37 (m, 2H),3.40 (s, 3H), 3.15 (dd, J = 632.2 13.7, 3.0 Hz, 1H), 1.57 (d, J = 7.0Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H); 2012

(3S,10S)-7-((3S,5R)- 4-(Acryloyl-d ₃ )-3,5- dimethylpiperazin-1-yl)-10-(2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1H NMR (400 MHz, MeOH- d₄) δ 8.14 (s, 1H), 7.30 (q,J = 8.0 Hz, 1H), 7.14 (t, J = 9.1 Hz, 2H), 5.42- 5.33 (m, 1H), 4.81-4.52(m, 2H), 4.40-4.2 (m, 2H), 3.70 (t, J = 9.1 Hz, 1H), 3.59 (dd, J = 9.2,4.9 Hz, 1H), 3.51 (dd, J = 13.5, 4.7 Hz, 1H), 3.45-3.40 (m, 1H), 3.39(s, 3H), 3.38-3.33 598.2 (m, 1H), 3.15 (dd, J = 13.6, 2.9 Hz, 1H), 1.57(d, J = 7.0 Hz, 3H), 1.42 (d, J = 6.9 Hz, 3H). 2013

(3S,10R)-7-((3S,5R)- 4-(Acryloyl-d₃)-3,5- dimethylpiperazin-1-yl)-10-(2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3-Hz, dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ 8.15 (s, 1H), 7.33 (q,J = 7.4 Hz, 1H), 7.14 (t, J = 7.5 2H), 5.41- 5.29 (m, 1H), 4.82-4.53 (brs, 2H), 4.39-4.19 (m, 2H), 3.72 (t, J = 9.2 Hz, 1H), 3.61 (dd, J = 9.2,4.8 Hz, 1H), 3.48 (dd, J = 13.5, 4.7 Hz, 1H), 3.44-3.33 (m, 2H), 3.39(s, 598.2 3H), 3.14 (dd, J = 13.6, 2.9 Hz, 1H), 1.58 (d, J = 6.9 Hz,3H), 1.42 (d, J = 7.0 Hz, 3H). 2014

(3S,10R)-7-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-10-(6-fluoro-1- methyl-1H-indazol-7- yl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]t1iazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ 8.22 (s, 1H), 8.16 (s,1H), 7.18 (dd, J = 8.0, 4.8 Hz, 1H), 6.97 (dd, J = 9.7, 8.0 Hz, 1H),6.85 (dd, J = 16.7, 10.5 Hz, 1H), 6.30 (dd, J = 16.6, 2.0 Hz, 1H), 5.81(dd, J = 10.6, 2.0 Hz, 1H), 5.39-5.31 (m, 1H), 4.84- 4.46 (m, 3H), 631.24.39 (d, J = 13.8 Hz, 1H), 4.3 (d, J = 13.6 Hz, 1H), 3.73-3.60 (m, 2H),3.56 (s, 3H), 3.55-3.38 (m, 3H), 3.36 (s, 2H), 3.35-3.33 (m, 1H), 3.15(dd, J = 13.7, 3.0 Hz, 1H), 1.60 (d, J = 7.0 Hz, 3H), 1.47- 1.39 (m,3H); 2015

(S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-10-(4-fluorophenyl)-3- ((trideuteriomethoxy) methyl)-9- (trifluoromethyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one ¹H NMR (400 MHz, CDCl3) δ8.06 (s, 1H), 7.23-7.15 (m, 4H), 6.62 (dd, J = 10.4 Hz, J = 16.4 Hz,1H), 6.41 (dd, J = 1.6 Hz, J = 16.8 Hz, 1H), 5.77 (dd, J = 2.0 Hz, J =10.4 Hz, 1H), 5.43-5.41 (m, 1H), 4.82-4.54 (m, 2H), 4.21- 4.16 (m, 2H),3.69-3.62 (m, 2H), 3.39-3.29 (m, 3H), 2.98- 580.2 2.94 (m, 1H), 1.62 (d,J = 7.2Hz, 3H), 1.47 (d, J = 7.2 Hz, 3H). 2016

(3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-10-(2,4-difluorophenyl)-3- (ethoxymethyl)-9- (trifluoromethyl)-2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one ¹H NMR (400 MHz, CDCl3) δ8.07 (s, 1H), 7.23-7.13 (m, 1H), 7.08-6.92 (m, 2H), 6.63 (dd, J = 16.8Hz, 6.0 Hz, 1H), 6.41 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.78 (dd, J = 10.8Hz, 1.6 Hz, 1H), 5.51- 5.38 (m, 1H), 5.00-4.40 (m, 2H), 4.25-4.14 (m,2H), 3.74- 609.2 3.47 (m, 4H), 3.43-3.28 (m, 3H), 3.07-2.97 (m, 1H),1.63 (d, J = 7.2 Hz, 3H), 1.48 (d, J = 6.4 Hz, 3H), 1.18 (t, J = 6.8 Hz,3H). 2017

(S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-3-(ethoxymethyl)- 10-(4-fluorophenyl)- 9-(trifluoromethyl)- 2H-[1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one ¹H NMR (400 MHz, CDCl3) δ8.06 (s, 1H), 7.25-7.14 (m, 4H), 6.63 (dd, J = 16.4 Hz, 10.8 Hz, 1H),6.41 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.78 (dd, J = 10.4 Hz, 2.0 Hz, 1H),5.47-5.37 (m, 1H), 4.90- 4.40 (m, 2H), 4.25-4.13 (m, 2H), 3.75-3.47 (m,4H), 3.43- 591.3 3.26 (m, 3H), 2.96 (dd, J = 13.6 Hz, 2.8 Hz, 1H), 1.62(d, J = 7.2 Hz, 3H), 1.47 (d, J = 6.8 Hz, 3H), 1.18 (t, J = 6.8 Hz, 3H).2018

(3S)-7-((3S,5R)-4- Acryloyl-3,5- dimethylpiperazin-1-yl)-10-(2,4-difluoro- 5-hydroxyphenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ 8.13 (s, 1H), 7.08 (t,J = 10.0 Hz, 1H), 6.90-6.72 (m, 2H), 6.29 (dd, J = 16.6, 2.0 Hz, 1H),5.80 (dd, J = 10.5, 2.0 Hz, 1H), 5.41-5.28 (m, 1H), 4.83- 4.50 (m, 2H),4.33 (d, J = 13.8 Hz, 1H), 4.25 (d, J = 13.6 Hz, 1H), 3.73 (t, J = 611.29.2 Hz, 1H), 3.61 (dd, J = 9.2, 4.7 Hz, 1H), 3.48 (dd, J = 13.5, 4.8 Hz,1H), 3.44-3.33 (m, 2H), 3.40 (s, 3H), 3.13 (dd, J = 13.8, 2.9 Hz, 1H),1.58 (d, J = 6.9 Hz, 3H), 1.42 (d, J = 6.9 Hz, 3H); 2019

(3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-chloro-2,4- difluorophenyl)-3- (trideuteriomethoxy)(methoxymethyl)-9- (trifluoromethyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one ¹H NMR (400 MHz, CDCl₃) δ 8.11 (s, 1H),7.35-7.27 (m, 1H), 7.15-7.09 (m, 1H), 6.72- 6.63 (m, 1H), 6.49-6.42 (m,1H), 5.84-5.80 (m, 1H), 5.52- 5.47 (m, 1H), 4.75-4.64 (m, 2H), 4.26-4.22(m, 2H), 3.75- 3.66 (m, 2H), 3.45-3.34 (m, 3H), 3.10-3.05 (m, 1H), 1.69-1.67 (m, 3H), 632.06 1.54-1.50 (m, 3H). 2020

(3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-10-(2,4-difluorophenyl)-3- ((trideuteriomethoxy) methyl)-9-(trifluoromethyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one ¹HNMR (400 MHz, CD₃OD) δ 8.08 (s, 1H), 7.21-7.15 (m, 1H), 7.00- 6.94 (m,2H), 6.65-5.58 (m, 1H), 6.44- 6.38 (m, 1H), 5.80-5.76 (m, 1H), 5.48-5.45 (m, 1H), 4.74-4.57 (m, 2H), 4.19-4.17 (m, 2H), 3.65- 3.58 (m, 2H),3.40-3.34 (m, 3H), 3.06- 598.2 2.98 (m, 1H), 1.63-1.60 (m, 3H), 1.47 (d,J = 7.2 Hz, 3H). 2021

(3S,10R)-7-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1- yl)-10-(2,4-difluorophenyl)-3- ((trideuteriomethoxy) methyl)-9-(trifluoromethyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one ¹HNMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.22-7.17 (m, 1H), 7.06-6.93 (m,2H), 6.64- 6.59 (m, 1H), 6.44-6.38 (m, 1H), 5.78 (dd, J = 10.4 Hz, 2.0Hz, 1H), 5.48- 5.45 (m, 1H), 4.66-4.63 (m, 2H), 4.23-4.19 (m, 2H), 3.70-3.60 (m, 2H), 3.40-3.30 (m, 3H), 3.04-2.99 (m, 1H), 1.63- 598.2 1.61 (m,3H), 1.47 (d, J = 6.8 Hz, 3H). 2022

(3S,10S)-7-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1- yl)-10-(2,4-difluorophenyl)-3- ((trideuteriomethoxy) methyl)-9-(trifluoromethyl)-2H- [1,4]thiazino[2,3,4- ij]quinazolin-5(3H)- one ¹HNMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.19-7.17 (m, 1H), 7.03-6.94 (m,2H), 6.64- 6.59 (m, 1H), 6.44-6.39 (m, 1H), 5.78 (dd, J = 12.4 Hz, 2.0Hz, 1H), 5.46- 5.43 (m, 1H), 4.76-4.64 (m, 2H), 4.21-4.16 (m, 2H), 3.67-3.65 (m, 2H), 3.40-3.32 (m, 3H), 3.06-3.01 (m, 1H), 1.63- 598.2 1.61 (m,3H), 1.52-1.46 (m, 3H). 2023

(3S,10R)-7-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-chloro-2,4- difluorophenyl)-3- ((methoxy- d₃)methyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.28-7.24(m, 1H), 7.07 (t, J = 8.8 Hz, 1H), 6.65-6.59 (m, 1H), 6.43-6.38 (m, 1H),5.78 (dd, J = 10.4 Hz, 1.6 Hz, 1H), 5.46-5.43 (m, 1H), 4.73-4.58 (m,2H), 4.21- 4.16 (m, 2H), 3.69-3.63 (m, 2H), 3.40-3.31 (m, 3H), 3.05-3.01 (m, 1H), 632.06 1.61 (d, J = 6.8 Hz, 3H), 1.48 (d, J = 6.8 Hz, 3H).2024

(3S,10S)-7-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-chloro-2,4- difluorophenyl)-3- (trideuteriomethoxy)(methoxymethyl)-9- (trifluoromethyl)-2H- [1,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H),7.28-7.25 (m, 1H), 7.07 (t, J = 8.8 Hz, 1H), 6.65-6.59 (m, 1H),6.43-6.38 (m, 1H), 5.78 (dd, J = 10.4 Hz, 1.6 Hz, 1H), 5.48-5.45 (m,1H), 4.80-4.43 (m, 2H), 4.21- 4.16 (m, 2H), 3.67-3.59 (m, 2H), 3.41-3.3(m, 3H), 3.04- 3.00 (m, 1H), 632.06 1.62-1.61 (m, 3H), 1.46 (d, J = 6.8Hz, 3H). 2025

(3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-bromo-2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ 8.15 (s, 1H), 7.63 (dt,J = 22.3, 7.4 Hz, 1H), 7.34 (td, J = 8.9, 4.4 Hz, 1H), 6.84 (dd, J =16.6, 10.6 Hz, 1H), 6.29 (dd, J 16.7, 2.0 Hz, 1H), 5.80 (d, J = 10.5 Hz,1H), 5.44-5.30 (m, 1H), 4.86-4.48 (m, 2H), 4.34 (t, J = 11.6 Hz, 673.21H), 4.26 (d, J = 13.6 Hz, 1H), 3.80-3.65 (m, 1H), 3.60 (td, J = 8.9,4.8 Hz, 1H), 3.50 (td, J = 12.8, 4.6 Hz, 1H), 3.45-3.35 (m, 5H), 3.16(ddd, J = 13.7, 5.8, 3.0 Hz, 1H), 1.63-1.52 (m, 3H), 1.42 (d, J = 6.9Hz, 3H). 2026

(3S)-7-((3S,5R)-4- Acryloyl-3,5- dimethylpiperazin-1-yl)-10-(2,4-difluoro- 5-hydroxyphenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ 8.13 (s, 1H), 7.08 (t,J = 10.0 Hz, 1H), 6.90-6.72 (m, 2H), 6.29 (dd, J = 16.6, 2.0 Hz, 1H),5.80 (dd, J = 10.5, 2.0 Hz, 1H), 5.41-5.28 (m, 1H), 4.83- 4.50 (m, 2H),4.33 (d, J = 13.8 Hz, 1H), 4.25 (d, J = 13.6 Hz, 1H), 3.73 (t, J = 9.2Hz, 1H), 3.61 (dd, J = 9.2, 4.7 Hz, 611.2 1H), 3.48 (dd, J = 13.5, 4.8Hz, 1H), 3.44-3.33 (m, 2H), 3.40 (s, 3H), 3.13 (dd, J = 13.8, 2.9 Hz,1H), 1.58 (d, J = 6.9 Hz, 3H), 1.42 (d, J = 6.9 Hz, 3H); 2028

(3S,10R)-7-((3S,5R)- 4-Acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-bromo-2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ 8.15 (s, 1H), 7.66 (t,J = 7.4 Hz, 1H), 7.34 (t, J = 9.0 Hz, 1H), 6.84 (dd, J = 16.7, 10.6 Hz,1H), 6.29 (dd, J = 16.7, 2.0 Hz, 1H), 5.80 (dd, J = 10.6, 2.0 Hz, 1H),5.41-5.31 (m, 1H), 4.86- 4.51 (m, 2H), 4.33 (d, J = 13.7 673.2 Hz, 1H),4.26 (d, J = 13.4 Hz, 1H), 3.75 (t, J = 9.2 Hz, 1H), 3.62 (dd, J = 9.2,4.8 Hz, 1H), 3.49 (dd, J = 13.5, 4.7 Hz, 1H), 3.45-3.36 (m, 2H), 3.40(s, 3H), 3.15 (dd, J = 13.7, 2.9 Hz, 1H), 1.57 (d, J = 7.1 Hz, 3H), 1.42(d, J = 7.0 Hz, 3H). 2029

(3S,10S)-7-((3S,5R)- 4-Acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-bromo-2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ 8.15 (s, 1H), 7.60 (t,J = 7.5 Hz, 1H), 7.35 (t, J = 8.9 Hz, 1H), 6.84 (dd, J = 16.7, 10.6 Hz,1H), 6.29 (dd, J = 16.7, 2.0 Hz, 1H), 5.80 (dd, J = 10.6, 2.0 Hz, 1H),5.43-5.32 (m, 1H), 4.86- 4.52 (m, 2H), 4.35 (d, J = 13.6 673.2 Hz, 1H),4.26 (d, J = 13.6 Hz, 1H), 3.69 (t, J = 9.1 Hz, 1H), 3.60 (dd, J = 9.2,4.9 Hz, 1H), 3.52 (dd, J = 13.6, 4.7 Hz, 1H), 3.47-3.35 (m, 2H), 3.39(s, 3H), 3.17 (dd, J = 13.7, 3.0 Hz, 1H), 1.56 (d, J = 6.9 Hz, 3H), 1.42(d, J = 6.9 Hz, 3H). 2030

(3S,10R)-7-((3S,5R)- 4-Acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-amino-2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1H NMR (400 MHz, MeOH- d₄) δ 8.12 (s, 1H), 6.98 (dd,J = 11.1, 9.1 Hz, 1H), 6.84 (dd, J = 16.7, 10.6 Hz, 1H), 6.71 (dd, J =9.5, 7.1 Hz, 1H), 6.29 (dd, J = 16.7, 2.0 Hz, 1H), 5.84-5.76 (m, 1H),5.41- 5.29 (m, 1H), 4.85-4.47 (m, 2H), 4.32 (d, J = 13.8 Hz, 1H), 610.24.25 (d, J = 13.7 Hz, 1H), 3.72 (d, J = 9.1 Hz, 1H), 3.61 (dd, J = 9.1,4.7 Hz, 1H), 3.47 (dd, J = 13.6, 4.6 Hz, 1H), 3.43-3.33 (m, 2H), 3.39(s, 3H), 3.12 (dd, J 13.7, 2.9 Hz, 1H), 1.58 (d, J = 6.9 Hz, 3H), 1.42(d, J = 6.9 Hz, 3H). 2031

(3S,10S)-7-((3S,5R)- 4-Acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-amino-2,4- difluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ 8.12 (s, 1H), 6.98 (dd,J = 11.0, 9.1 Hz, 1H), 6.84 (dd, J = 16.6, 10.6 Hz, 1H), 6.67 (dd, J =9.5, 7.1 Hz, 1H), 6.29 (dd, J = 16.6, 2.1 Hz, 1H), 5.80 (dd, J = 10.5,2.0 Hz, 1H), 5.43-5.31 (m, 1H), 4.85- 4.50 (m, 2H), 4.33 (d, J = 13.6610.2 Hz, 1H), 4.25 (d, J = 13.6 Hz, 1H), 3.70 (t, J = 9.1 Hz, 1H), 3.58(dd, J = 9.2, 4.9 Hz, 1H), 3.48 (dd, J = 13.5, 4.7 Hz, 1H), 3.43-3.33(m, 2H), 3.39 (s, 3H), 3.14 (dd, J = 13.6, 2.9 Hz, 1H), 1.57 (d, J = 6.9Hz, 3H), 1.42 (d, J = 6.9 Hz, 3H). 2033

(3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(2,4-difluoro- 5-iodophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ 8.14 (s, 1H), 7.76 (dt,J = 18.4, 7.3 Hz, 1H), 7.25 (td, J = 8.7, 4.1 Hz, 1H), 6.84 (dd, J =16.7, 10.6 Hz, 1H), 6.29 (dd, J = 16.7, 2.0 Hz, 1H), 5.80 (dd, J = 10.6,1.9 Hz, 1H), 5.44-5.3 (m, 1H), 4.86- 4.46 (m, 2H), 4.41-4.30 (m, 721.21H), 4.26 (d, J = 13.5 Hz, 1H), 3.72 (dt, J = 22.6, 9.2 Hz, 1H), 3.60(td, J = 9.6, 4.8 Hz, 1H), 3.50 (td, J = 12.7, 4.7 Hz, 1H), 3.45-3.42(m, 1H), 3.41- 3.35 (m, 4H), 3.16 (ddd, J = 13.7, 7.9, 2.9 Hz, 1H), 1.57(dd, J = 7.1, 3.2 Hz, 3H), 1.42 (d, J = 6.9 Hz, 3H). 2034

(R)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-3-((dimethylamino) methyl)-11-(4- fluorophenyl)-10- (trifluoromethyl)-3,4-dihydro- [1,4]thiazepino[2,3,4- ij]quinazolin-6(2H)- one ¹H NMR (400MHz, CDCl₃) δ 8.06 (s, 1H), 7.22-7.15 (m, 4H), 6.66-6.59 (m, 1H), 6.41(d, J = 16.4 Hz, 1H), 5.77 (d, J = 10.4 Hz, 1H), 4.84-4.44 (m, 3H),4.27-3.99 (m, 3H), 3.37- 3.19 (m, 3H), 3.09-2.97 (m, 1H), 2.68-2.44 (m,1H), 2.30- 2.21 (m, 8H), 1.59-1.51 (m, 6H) 603.2 2035

(S)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-3-((dimethylamino) methyl)-11-(4- fluorophenyl)-10- (trifluoromethyl)-3,4-dihydro- [1,4]thiazepino[2,3,4- ij]quinazolin-6(2H)- one ¹H NMR (400MHz, CDCl₃) δ 8.06 (s, 1H), 7.22-7.15 (m, 4H), 6.66-6.59 (m, 1H), 6.41(d, J = 16.8 Hz, 1H), 5.77 (d, J = 10.4 Hz, 1H), 4.86-4.45 (m, 3H),4.32-3.95 (m, 3H), 3.41- 3.20 (m, 3H), 3.05-3.02 (m, 1H), 2.67-2.42 (m,1H), 2.30- 2.21 (m, 8H), 1.58-1.51 (m, 6H). 603.2 2036

8′-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1- yl)-11′-(2,4-difluoro-5-iodophenyl)-10′ (trifluoromethyl)- 2′H,4′H,6′H- spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4- ij]quinazolin]-6′-one ¹H NMR (400 MHz, MeOH- d₄)δ 7.96 (s, 1H), 7.82-7.65 (m, 1H), 7.21 (td, J = 8.7, 3.1 Hz, 1H), 6.91-6.70 (m, 1H), 6.34-6.21 (m, 1H), 5.80 (ddd, J = 9.7, 7.2, 2.0 Hz, 1H),4.86- 4.58 (m, 3H), 4.57-4.36 (m, 3H), 4.35-3.99 (m, 2H), 3.98- 3.68 (m,2H), 3.67-3.36 (m, 3H), 1.53-1.2 0 (m, 6H). 733.1 2037

(3S)-7-((4aR,7aS)-4- Acryloyl-6,6- dioxidohexahydro- thieno[3,4-b]pyrazin-1(2H)-yl)- 10-(5-chloro-2,4- difluorophenyl)-3-(methoxymethyl)-9- (trifluoromethyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one ¹H NMR (400 MHz, CDCl₃) δ 7.95(s, 1H), 7.25-7.16 (m, 1H), 7.13-7.04 (m, 1H), 6.60- 6.41 (m, 2H), 5.89(dd, J = 16.0, 4.0 Hz, 1H), 5.72-5.20 (m, 3H), 4.85- 4.75 (m, 1H),4.20-3.86 (m, 3H), 3.83-3.71 (m, 2H), 3.70- 3.60 (m, 2H), 3.60-3.45 (m,691.0 3H), 3.43-3.30 (m, 3H), 3.11- 2.97 (m, 1H) 2038

(R)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-11-(4-fluorophenyl)-3- (((S)-3- fluoropyrrolidin-1- yl)methyl)-10-(trifluoromethyl)-3,4- dihydro- [1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)- one ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H),7.22-7.15 (m, 4H), 6.66-6.59 (m, 1H), 6.41 (d, J = 16.4 Hz, 1H), 5.78(d, J = 10.4 Hz, 1H), 5.20-5.06 (m, 1H), 4.84-4.45 (m, 3H), 4.24- 4.14(m, 3H), 3.37-3.21 (m, 3H), 3.12-3.03 (m, 1H), 2.91- 2.80 (m, 2H),2.72-2.54 (m, 3H), 2.46-2.33 (m, 2H), 2.16- 1.93 (m, 2H), 647.21.62-1.51 (m, 6H). 2039

(S)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-11-(4-fluorophenyl)-3- (((S)-3- fluoropyrrolidin-1- yl)methyl)-10-(trifluoromethyl)-3,4- dihydro- [1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)- one ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H),7.21-7.15 (m, 4H), 6.66-6.59 (m, 1H), 6.41 (d, J = 16.4 Hz, 1H), 5.78(d, J = 10.8 Hz, 1H), 5.18-5.04 (m, 1H), 4.80-4.41 (m, 3H), 4.26- 4.05(m, 3H), 3.37-3.22 (m, 3H), 3.13-3.02 (m, 1H), 2.86- 2.72 (m, 3H),2.64-2.53 (m, 2H), 2.43-2.26 (m, 2H), 2.16- 647.2 1.91 (m, 2H),1.59-1.51 (m, 6H). 2040

(3S)-7-(9-Acryloyl-3- thia-7,9- diazabicyclo[3.3.1] nonan-7-yl)-10-(2,4-difluorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one ¹H NMR (400 MHz, CDCl3) δ8.01-7.94 (m, 1H), 7.21-7.17 (m, 1H), 7.07- 6.93 (m, 2H), 6.63-6.54 (m,1H), 6.42-6.36 (m, 1H), 5.86- 5.81 (m, 1H), 5.49-5.31 (m, 1H), 5.20-5.08(m, 1H), 4.97- 4.64 (m, 1H), 4.59-4.38 (m, 2H), 3.95-3.82 (m, 1H), 3.75-625.1 3.55 (m, 3H), 3.45-3.25 (m, 6H), 3.08-2.95 (m, 1H), 2.84- 2.68 (m,1H), 2.62-2.51 (m, 1H) 2041

1-(3-((3S,10R)-7- ((3S,5R)-4-acryloyl- 3,5- dimethylpiperazin-1- yl)-3-(methoxymethyl)-5- oxo-9- (trifluoromethyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-10-yl)- 4- fluorophenyl)cyclo-butane-1-carbonitrile ¹H NMR (400 MHz, MeOH- d₄) δ 8.16 (s, 1H),7.72-7.63 (m, 1H), 7.41 (dd, J = 6.5, 2.5 Hz, 1H), 7.32 (t, J = 8.9 Hz,1H), 6.84 (dd, J = 16.7, 10.6 Hz, 1H), 6.29 (dd, J = 16.7, 2.0 Hz, 1H),5.80 (dd, J = 10.6, 2.0 Hz, 1H), 5.42-5.3 (m, 1H), 4.84- 4.51 (br s,2H), 656.3 4.33 (d, J = 13.9 Hz, 1H), 4.27 (d, J = 13.6 Hz, 1H), 3.75(t, J = 9.2 Hz, 1H), 3.61 (dd, J = 9.3, 4.8 Hz, 1H), 3.52-3.4 (m, 2H),3.39 (s, 3H), 3.38-3.33 (m, 1H), 3.15 (dd, J = 13.7, 3.0 Hz, 1H),2.88-2.75 (m, 2H), 2.74-2.61 (m, 2H), 2.49- 2.32 (m, 1H), 2.18-2.04 (m,1H), 1.58 (d, J = 6.9 Hz, 3H), 1.43 (d, J = 6.9 Hz, 3H). 2042

1-(3-((3S,10S)-7- ((3S,5R)-4-acryloyl- 3,5- dimethylpiperazin-1- yl)-3-(methoxymethyl)-5- oxo-9- (trifluoromethyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-10-yl)- 4- fluorophenyl)cyclo-butane-1-carbonitrile 1H NMR (400 MHz, MeOH- d₄) δ 8.16 (s, 1H),7.73-7.63 (m, 1H), 7.39- 7.28 (m, 2H), 6.84 (dd, J = 16.7, 10.6 Hz, 1H),6.29 (dd, J = 16.7, 1.9 Hz, 1H), 5.80 (dd, J = 10.5, 2.0 Hz, 1H),5.43-5.31 (m, 1H), 4.84- 4.52 (m, 2H), 4.36 (d, J = 13.5 Hz, 1H), 4.27656.3 (d, J = 13.5 Hz, 1H), 3.71 (t, J = 9.1 Hz, 1H), 3.60 (dd, J = 9.2,4.9 Hz, 1H), 3.52 (dd, J = 13.5, 4.7 Hz, 1H), 3.46-3.4 (m, 1H), 3.39 (s,3H), 3.38-3.33 (m, 1H), 3.16 (dd, J = 13.7, 3.0 Hz, 1H), 2.87-2.76 (m,2H), 2.74-2.62 (m, 2H), 2.48- 2.33 (m, 1H), 2.18-2.04 (m, 1H), 1.57 (d,J = 6.9 Hz, 3H), 1.42 (d, J = 6.8 Hz, 3H). 2043

(3S)-7-(9-Acryloyl-3- thia-7,9- diazabicyclo[3.3.1] nonan-7-yl)-10-(5-chloro-2.4- difluorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino|[2,3,4- ij]quinazolin-5-one ¹H NMR (400 MHz,CDCl₃) δ 8.05-7.91 (m, 1H), 7.32-7.28 (m, 1H), 7.10- 7.02 (m, 1H),6.64-6.52 (m, 1H), 6.47-6.34 (m, 1H), 5.88- 5.83 (m, 1H), 5.45-5.39 (m,1H), 5.13-5.09 (m, 1H), 4.94- 4.87 (m, 1H), 4.72-4.39 (m, 3H), 3.92-3.86659.0 (m, 1H), 3.69- 3.62 (m, 3H), 3.42-3.39 (m, 2H), 3.37-3.35 (m, 1H),3.30- 3.23 (m, 1H), 3.08-3.03 (m, 1H), 2.89-2.46 (m, 3H)  2044a

(3S)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- (pyrimidin-2-yloxy)-10-(trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one 1H NMR (400 MHz, CDCl₃) δ 8.53 (d, J = 4.8 Hz, 2H),8.10 (s, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 8.8 Hz, 1H), 6.99(t, J = 4.8 Hz, 1H), 6.63 (dd, J = 10.4, 16.8 Hz, 1H), 6.42 (dd, J =1.6, 16.4 Hz, 1H), 5.83-5.67 (m, 2H), 5.22- 4.44 (m, 4H), 4.18 (d, J =13.2 Hz, 2H), 3.68- 3.47 (m, 1H), 3.46-3.24 (m, 3H), 1.64-1.54 693.0 (m,6H) 2045

(3S,11S)-8-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- (pyrimidin-2-yloxy)-10-(trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl₃) δ 8.53 (d, J = 4.8 Hz, 2H),8.10 (s, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 8.8 Hz, 1H), 6.99(t, J = 4.8 Hz, 1H), 6.63 (dd, J = 10.4, 16.8 Hz, 1H), 6.42 (dd, J =1.6, 16.4 Hz, 1H), 5.83-5.67 (m, 2H), 5.22- 4.44 (m, 4H), 4.18 (d, J =13.2 Hz, 2H), 3.68- 3.47 (m, 1H), 3.46-3.24 (m, 3H), 1.64-1.54 693.0 (m,6H) 2046

(3S,11R)-8-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- (pyrimidin-2-yloxy)-10-(trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl₃) δ 8.54 (d, J = 4.8 Hz, 2H),8.10 (s, 1H), 7.31- 7.27 (m, 1H), 7.07 (t, J = 8.8 Hz, 1H), 6.99 (t, J =4.8 Hz, 1H), 6.63 (dd, J = 10.4, 16.8 Hz, 1H), 6.42 (dd, J = 2.0, 16.8Hz, 1H), 5.82-5.62 (m, 2H), 5.07- 4.40 (m, 4H), 4.18 (d, J = 13.2 Hz,2H), 3.57- 3.31 (m, 4H), 1.91-1.54 (m, 6H) 693.0 2047

(3S)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- ((5-methylisoxazol-3-yl)oxy)-10- (trifluoromethyl)-3,4- dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.25 (m,1H), 7.06 (m, 1H), 6.63 (dd, J₁ = 17.2 Hz, J₂ = 10.8 Hz, 1H), 6.42 (dd,J₁ = 2.0 Hz, J₂ = 16.8 Hz, 1H), 5.79 (dd, J₁ = 2.0 Hz, J₂ = 10.4 Hz,1H), 5.70 (s, 1H), 5.67 (s, 1H), 4.95~4.32 (m, 4H), 4.24~4.21 (m, 2H),3.43~ 3.36 (m, 3H), 3.17~3.14 (m, 696.2 1H), 2.32 (s, 3H), 1.62-1.58 (m,3H), 1.52- 1.49 (s, 3H) 2048

(3S,11R)-8-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- (pyrimidin-2- ylamino)-10-(trifluoromethyl)-3,4- dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl3) δ 8.44-8.19 (m, 2H), 8.12(s, 1H), 7.27-7.23 (m, 2H), 7.06 (br t, J = 8.8 Hz, 1H), 6.80-6.59 (m,2H), 6.42 (dd, J = 1.6, 16.8 Hz, 1H), 5.79 (dd, J = 1.6, 10.4 Hz, 1H),5.12-4.61 (m, 4H), 4.59- 4.34 (m, 1H), 4.27-4.15 (m, 2H), 3.77-3.57 (m,1H), 3.46- 3.35 (m, 2H), 3.32-3.13 (m, 692.0 1H), 1.55 (br s, 6H) 2049

(3S)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- (isothiazol-3-yloxy)-10-(trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, DMSO- d6) δ ppm 1.41 (br s, 6H)3.21- 3.31 (m, 4H) 4.07 (br d, J = 12.60 Hz, 2H) 4.30-4.99 (m, 4H) 5.46(br d, J = 5.20 Hz, 1H) 5.69- 5.80 (m, 1H) 6.15-6.30 (m, 1H) 6.67-6.90(m, 2H) 7.69- 7.87 (m, 2H) 8.07 (br s, 1H) 8.45-8.52 (m, 1H) 8.92 (dd, J= 4.80, 2.40 Hz, 1H) 698.1 2050

1-(5-((3S,10R)-7- ((3S,5R)-4-acryloyl- 3,5- dimethylpiperazin-1- yl)-3-(methoxymethyl)-5- oxo-9- (trifluoromethyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-10-yl)- 2,4- difluorophenyl)cyclopropane-1- carbonitrile ¹H NMR (400 MHz, MeOH- d₄) δ 8.15 (s, 1H), 7.48(t, J = 7.8 Hz, 1H), 7.27 (t, J = 9.7 Hz, 1H), 6.84 (dd, J = 16.7, 10.6Hz, 1H), 6.29 (dd, J = 16.7, 2.0 Hz, 1H), 5.80 (dd, J = 10.6, 2.0 Hz,1H), 5.41-5.30 (m, 1H), 4.85- 4.52 (br s, 2H), 4.33 (d, J = 13.6 660.2Hz, 1H), 4.26 (d, J = 13.6 Hz, 1H), 3.75 (t, J = 9.2 Hz, 1H), 3.62 (dd,J = 9.3, 4.8 Hz, 1H), 3.49 (dd, J = 13.5, 4.7 Hz, 1H), 3.46-3.4 (m, 1H),3.40 (s, 3H), 3.39-3.34 (m, 1H), 3.15 (dd, J = 13.7, 3.0 Hz, 1H),1.78-1.69 (m, 2H), 1.57 (d, J = 7.0 Hz, 3H), 1.49-1.36 (m, 5H). 2051

1-(5-((3S,10S)-7- ((3S,5R)-4-acryloyl- 3,5- dimethylpiperazin-1- yl)-3-(methoxymethyl)-5- oxo-9- (trifluoromethyl)-2,3- dihydro-5H-[1,4]t1iazino[2,3,4- ij]quinazolin-10-yl)- 2,4- difluorophenyl)cyclopropane-1- carbonitrile ¹H NMR (400 MHz, MeOH- d₄) δ 8.14 (s, 1H), 7.42(t, J = 7.9 Hz, 1H), 7.28 (t, J = 9.7 Hz, 1H), 6.84 (dd, J = 16.7, 10.6Hz, 1H), 6.29 (dd, J = 16.7, 2.0 Hz, 1H), 5.80 (d, J = 11.4 Hz, 1H),5.44-5.30 (m, 1H), 4.84-4.54 (m, 2H), 4.36 660.2 (d, J = 13.4 Hz, 1H),4.26 (d, J = 13.5 Hz, 1H), 3.70 (t, J = 9.1 Hz, 1H), 3.59 (dd, J = 9.3,4.9 Hz, 1H), 3.52 (dd, J = 13.6, 4.7 Hz, 1H), 3.49-3.40 (m, 1H), 3.39(s, 3H), 3.38-3.33 (m, 1H), 3.15 (dd, J = 13.8, 3.1 Hz, 1H), 1.77-1.69(m, 2H), 1.56 (d, J = 6.9 Hz, 3H), 1.48-1.36 (m, 5H). 2053

(3S,11R)-8-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- (isothiazol-3-yloxy)-10-(trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl3) δ: 8.38 (d, J = 4.8 Hz, 1H),8.04 (s, 1H), 7.28-7.19 (m, 1H), 6.99 (t, J = 8.8 Hz, 1H), 6.63-6.50 (m,2H), 6.42-6.27 (m, 1H), 5.71 (br d, J = 10.8 Hz, 1H), 5.55 (br s, 1H),4.81 (br d, J = 10.4 Hz, 1H), 4.68- 4.56 (m, 1H), 4.10 (br t, J = 13.2Hz, 2H), 3.53-3.27 (m, 697.8 4H), 1.68 (br d, J = 1.2 Hz, 2H), 1.48 (brs, 6H) 2054

(3S,11R)-8-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- (isothiazol-3-yloxy)-10-(trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one 1H NMR (400 MHz, CHLOROFORM- d) δ: 8.38 (d, J = 4.8Hz, 1H), 8.03 (s, 1H), 7.26-7.20 (m, 1H), 7.03-6.93 (m, 1H), 6.69- 6.50(m, 2H), 6.34 (dd, J = 2.0, 16.8 Hz, 1H), 5.72 (dd, J = 2.0, 10.4 Hz,1H), 5.58 (br s, 1H), 4.83 (br d, J = 1.2 Hz, 1H), 4.67-4.57 (m, 1H),4.14-4.08 (m, 2H), 3.42- 3.24 (m, 4H), 697.8 1.64 (br s, 2H), 1.48 (brt, J = 5.6 Hz, 6H) 2055

(3S,11R)-8-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- (pyrimidin-2- ylamino)-10-(trifluoromethyl)-3,4- dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl3) δ, 8.44-8.19 (m, 2H), 8.12(s, 1H), 7.27-7.23 (m, 2H), 7.06 (br t, J = 8.8 Hz, 1H), 6.80-6.59 (m,2H), 6.42 (dd, J = 1.6, 16.8 Hz, 1H), 5.79 (dd, J = 1.6, 10.4 Hz, 1H),5.12-4.61 (m, 4H), 4.59- 4.34 (m, 1H), 4.27-4.15 (m, 2H), 3.77-3.57 (m,1H), 3.46- 3.35 (m, 2H), 3.32-3.13 (m, 692.0 1H), 1.55 (br s, 6H) 2056

(3S,10R)-7-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-10-(2,4-difluoro- 5-iodophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ 8.14 (s, 1H), 7.78 (t,J = 7.3 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 6.84 (dd, J = 16.7, 10.6 Hz,1H), 6.29 (d, J = 16.0 Hz, 1H), 5.8 (dd, J = 10.5, 2.0 Hz, 1H),5.42-5.30 (m, 1H), 4.84-4.51 (br s, 2H), 4.33 (d, J = 13.3 Hz, 721.21H), 4.26 (d, J = 13.5 Hz, 1H), 4.20 (s, 1H), 3.80-3.66 (m, 1H),3.65-3.56 (m, 1H), 3.55- 3.42 (m, 2H), 3.41 (s, 3H), 3.40-3.35 (m, 2H),3.20-3.1 (m, 1H), 1.57 (d, J = 6.8 Hz, 3H), 1.42 (d, J = 6.9 Hz, 3H).2057

(3S,10S)-7-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-10-(2,4-difluoro- 5-iodophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ 8.14 (s, 1H), 7.73 (t,J = 7.4 Hz, 1H), 7.25 (dd, J = 9.4, 8.1 Hz, 1H), 6.84 (dd, J = 16.7,10.6 Hz, 1H), 6.29 (dd, J = 16.7, 2.0 Hz, 1H), 5.80 (dd, J = 10.6, 2.0Hz, 1H), 5.43-5.31 (m, 1H), 4.84- 4.55 (m, 2H), 4.35 (d, J = 13.5 721.2Hz, 1H), 4.26 (d, J = 13.5 Hz, 1H), 4.18 (s, 1H), 3.69 (t, J = 9.2 Hz,1H), 3.59 (dd, J = 9.3, 4.9 Hz, 1H), 3.51 (dd, J = 13.5, 4.8 Hz, 1H),3.46-3.38 (m, 1H), 3.39 (s, 3H), 3.38-3.35 (m, 1H), 3.17 (dd, J = 13.6,3.0 Hz, 1H), 1.57 (d, J = 6.9 Hz, 3H), 1.42 (d, J = 6.9 Hz, 3H). 2058

(S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-10-(4-chlorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ8.13 (s, 1H), 7.57-7.44 (m, 2H), 7.32- 7.17 (m, 2H), 6.84 (dd, J = 16.7,10.6 Hz, 1H), 6.29 (dd, J = 16.6, 2.0 Hz, 1H), 5.80 (dd, J = 10.7, 2.0Hz, 1H), 5.40-5.28 (m, 1H), 4.85- 4.50 (br s, 2H), 4.34 (d, J = 13.6 Hz,1H), 4.26 593.2 (d, J = 13.6 Hz, 1H), 3.73 (t, J = 9.2 Hz, 1H), 3.60(dd, J = 9.2, 4.8 Hz, 1H), 3.49 (dd, J = 13.5, 4.7 Hz, 1H), 3.44-3.33(m, 1H), 3.39 (s, 3H), 3.09 (dd, J = 13.6, 2.9 Hz, 1H), 1.57 (d, J = 6.9Hz, 3H), 1.42 (d, J = 6.9 Hz, 3H). 2059

(3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(4-chloro-2- fluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1H NMR (400 MHz, MeOH- d₄) δ 8.15 (s, 1H), 7.45-7.35(m, 2H), 7.34- 7.22 (m, 1H), 6.84 (dd, J = 16.7, 10.6 Hz, 1H), 6.29 (dd,J = 16.7, 2.0 Hz, 1H), 5.80 (dd, J = 10.6, 2.0 Hz, 1H), 5.44-5.3 (m,1H), 4.84- 4.47 (br s, 2H), 4.42-4.30 (m, 1H), 4.26 (d, J = 611.2 13.5Hz, 1H), 3.71 (q, J = 9.0 Hz, 1H), 3.65- 3.55 (m, 1H), 3.55-3.45 (m,1H), 3.45-3.34 (m, 2H), 3.39 (s, 1H), 3.20-3.10 (m, 1H), 1.57 (dd, J =7.0, 3.4 Hz, 3H), 1.42 (d, J = 6.9 Hz, 3H). 2060

(3S)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- (pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4- dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CHLOROFORM- d) δ ppm 1.50 (d, J =6.8 Hz, 3H) 1.63 (d, J = 6.8 Hz, 3H) 3.19-3.39 (m, 1H) 3.40- 3.49 (m,4H) 4.20-4.23 (m, 2H) 4.59-4.60 (m, 2H) 4.61- 4.62 (m, 1H) 5.78-5.81 (m,2H) 6.40-6.45 (m, 1H) 6.60- 6.67 (m, 1H) 7.06-7.08 (m, 1H) 7.27 (s, 1H)8.07-8.19 693.2 (m, 4H) 2061

(3S)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- (pyridazin-3-yloxy)-10-(trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl3) δ 8.86 (dd, J = 1.2, 4.4 Hz,1H), 8.12-8.08 (m, 1H), 7.40 (dd, J = 4.4, 8.8 Hz, 1H), 7.31- 7.28 (m,1H), 7.07 (t, J = 8.8 Hz, 1H), 7.03- 6.97 (m, 1H), 6.68-6.59 (m, 1H),6.43 (dd, J = 2.0, 16.8 Hz, 1H), 5.90-5.82 (m, 1H), 5.79 (dd, J = 2.0,10.0 Hz, 1H), 4.90-4.85 (m, 1H), 4.81-4.56 693.0 (m, 3H), 4.26- 4.19 (m,2H), 3.48-3.39 (m, 2H), 3.35 (dd, J = 4.4, 13.6 Hz, 1H), 3.25-3.18 (m,1H), 1.61 (d, J = 6.8 Hz, 3H), 1.52 (d, J = 6.8 Hz, 3H) 2062

(S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-10-(4-bromophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ8.13 (s, 1H), 7.72-7.61 (m, 2H), 7.26- 7.12 (m, 2H), 6.84 (dd, J = 16.6,10.6 Hz, 1H), 6.29 (dd, J = 16.7, 2.0 Hz, 1H), 5.80 (dd, J = 10.6, 2.0Hz, 1H), 5.40-5.29 (m, 1H), 4.86- 4.49 (br s, 2H), 4.34 (d, J = 13.6 Hz,1H), 4.26 637.2 (d, J = 13.6 Hz, 1H), 3.73 (t, J = 9.2 Hz, 1H), 3.60(dd, J = 9.2, 4.8 Hz, 1H), 3.49 (dd, J = 13.6, 4.7 Hz, 1H), 3.44-3.32(m, 2H), 3.39 (s, 3H), 3.09 (dd, J = 13.7, 2.9 Hz, 1H), 1.57 (d, J = 6.9Hz, 3H), 1.41 (d, J = 6.9 Hz, 3H). 2063

(3S)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- (pyrimidin-4-yloxy)-10-(trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl₃) δ, 8.90 (s, 1H), 8.61-8.49(m, 1H), 8.09 (s, 1H), 7.27 (br s, 2H), 7.12-7.03 (m, 1H), 6.96 (q, J =5.6 Hz, 1H), 6.68-6.57 (m, 1H), 6.41 (dd, J = 1.6, 16.8 Hz, 1H),5.84-5.73 (m, 2H), 4.81-4.72 (m, 2H), 4.71- 4.59 (m, 1H), 4.27-4.14 (m,2H), 3.53-3.31 (m, 3H), 3.25- 3.13 (m, 1H), 693.2 1.61 (d, J = 6.8 Hz,3H), 1.49- 1.44 (m, 3H) 2064

(3S)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-bromo-2,4- difluorophenyl)-3- (pyridin-2-yloxy)-10-(trifluoromethyl)-3,4- dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl3) δ = 8.25-8.01 (m, 2H), 7.75-7.59 (m, 1H), 7.48-7.36 (m, 1H), 7.10-6.91 (m, 2H), 6.89- 6.75 (m, 1H),6.63 (dd, J = 16.6, 10.6, 1H), 6.42 (dd, J = 16.6, 2.0, 1H), 5.93-5.71(m, 2H), 5.04- 4.48 (m, 4H), 4.28-4.06 (m, 2H), 3.67-3.25 (m, 4H), 1.71-1.36 (m, 6H) 736.0 2065

(3S)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-bromo-2,4- difluorophenyl)-3- (pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4- dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 8.15 (s,1H), 8.11-8.07 (m, 2H), 7.46-74.42 (m, 1H), 7.26 (m, 1H), 6.63 (dd, J =10.4, 16.8 Hz, 1H), 6.42 (dd, J = 1.6, 16.4 Hz, 1H), 5.83-5.67 (d, J =10.4 Hz, 2H), 4.90-4.50 (m, 4H), 4.25 (m, 2H), 3.68-3.24 (m, 4H), 1.75-1.30 (m, 6H) 737.1 2066

(3S)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-bromo-2,4- difluorophenyl)-3- (pyrimidin-2-yloxy)-10-(trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl3) δ = 8.54 (d, J = 4.0, 2H),8.10 (s, 1H), 7.49- 7.36 (m, 1H), 7.07-6.98 (m, 2H), 6.63 (dd, J = 16.4,10.4, 1H), 6.42 (d, J = 16.0, 1H), 5.79 (d, J = 10.0, 1H), 5.74 (m, 1H),4.93-4.67 (m, 4H), 4.19- 4.15 (m, 2H), 3.66-3.36 (m, 4H), 1.75 (m, 3H),1.55 (m, 3H). 736.9/ 739.0 2067

(3S,11S)-8-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- (pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4- dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl3) δ ppm 1.50 (d, J = 7.2 Hz,3H) 1.62 (s, 3H) 3.18-3.23 (m, 1H) 3.36-3.48 (m, 3H) 3.70- 3.75 (m, 1H)4.22 (d, J = 12.4 Hz, 2H) 4.57 4.61 (m, 2H) 4.67 (d, J = 10.4 Hz, 1H)5.76 (d, J = 2.8 Hz, 1H) 5.78-5.81 (m, 1H) 6.40- 6.45 (m, 1H) 6.60-6.67(m, 1H) 7.08 (t, J = 8.8 Hz, 1H) 693.2 7.23-7.27 (m, 1H) 8.06 (s, 1H)8.09 (s, 1H) 8.17 (d, J = 2.8 Hz, 1H) 8.25 (s, 1H) 2068

(3S,11R)-8-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- (pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4- dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl3) δ ppm 1.50 (d, J = 6.8 Hz,3H) 1.63 (d, J = 6.8 Hz, 3H) 3.19- 3.39 (m, 1H) 3.40-3.49 (m, 4H)4.20-4.23 (m, 2H) 4.59- 4.60 (m, 2H) 4.61-4.62 (m, 1H) 5.78-5.81 (m, 2H)6.40- 6.45 (m, 1H) 6.60-6.67 (m, 1H) 7.06-7.08 (m, 1H) 7.27 (s, 1H)8.07-8.19 (m, 4H) 693.2 2069

(3S,11S)-8-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- (pyridin-2-yloxy)-10-(trifluoromethyl)-3,4- dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl₃) δ, 8.12 (m, 2H), 7.58 (ddd,J = 4.0, 8.0, 8.0 Hz), 7.27 (s, 1H), 7.06 (J = 8.8, 8.8 Hz, 1H), 6.89(m, 1H), 6.76 (d, J = 10.8 Hz), 6.63 (dd, J = 10.8, 16.4 Hz), 6.41 (dd,J = 1.6, 16.4 Hz, 1H), 5.78 (dd, J = 1.6, 10.8 Hz, 1H), 5.74 (m, 1H),4.91- 4.58 (m, 4H), 4.17 (m, 2H), 3.56-3.33 (m, 692.1 4H), 1.57 (m, 6H)2070

(3S,11R)-8-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- (pyridin-2-yloxy)-10-(trifluoromethyl)-3,4- dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl₃) δ 8.12 (m, 2H), 7.58 (ddd, J= 4.0, 8.0, 8.0 Hz), 7.27 (s, 1H), 7.06 (J = 8.8, 8.8 Hz, 1H), 6.89 (m,1H), 6.76 (d, J = 10.8 Hz), 6.63 (dd, J = 10.8, 16.4 Hz), 6.41 (dd, J =1.6, 16.4 Hz, 1H), 5.78 (dd, J = 1.6, 10.8 Hz, 1H), 5.74 (m, 1H), 4.91-4.58 (m, 4H), 4.17 (m, 2H), 3.56-3.33 (m, 692.1 4H), 1.57 (m, 6H) 2071

(S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-3-(methoxymethyl)-10- phenyl-9- (trifluoromethyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one 1H NMR (400 MHz, MeOH- d₄) δ8.13 (s, 1H), 7.56-7.43 (m, 3H), 7.31- 7.16 (m, 2H), 6.84 (dd, J = 16.7,10.6 Hz, 1H), 6.29 (dd, J = 16.7, 1.9 Hz, 1H), 5.80 (dd, J = 10.5, 2.0Hz, 1H), 5.40-5.28 (m, 1H), 4.86- 4.47 (br s, 2H), 4.34 (d, J = 13.7 Hz,1H), 4.26 559.2 (d, J = 13.5 Hz, 1H), 3.73 (t, J = 9.2 Hz, 1H), 3.60(dd, J = 9.2, 4.8 Hz, 1H), 3.47 (dd, J = 13.5, 4.7 Hz, 1H), 3.43-3.33(m, 2H), 3.39 (s, 3H), 3.08 (dd, J = 13.7, 2.9 Hz, 1H), 1.58 (d, J = 6.9Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H). 2072

(3S,10S)-7-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-10-(4-chloro-2- fluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ 8.14 (s, 1H), 7.46-7.35(m, 2H), 7.27 (t, J = 8.1 Hz, 1H), 6.84 (dd, J = 16.6, 10.6 Hz, 1H),6.29 (dd, J = 16.6, 2.0 Hz, 1H), 5.80 (dd, J = 10.6, 2.0 Hz, 1H),5.43-5.3 (m, 1H), 4.84- 4.48 (br s, 2H), 4.35 (d, J = 13.7 Hz, 1H), 4.26611.2 (d, J = 13.6 Hz, 1H), 3.70 (t, J = 9.1 Hz, 1H), 3.59 (dd, J = 9.2,4.9 Hz, 1H), 3.51 (dd, J = 13.6, 4.7 Hz, 1H), 3.46-3.33 (m, 2H), 3.39(s, 3H), 3.15 (dd, J = 13.7, 2.9 Hz, 1H), 1.61-1.52 (m, 3H), 1.42 (d, J= 6.9 Hz, 3H). 2073

(3S,10R)-7-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-10-(4-chloro-2- fluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ 8.15 (s, 1H), 7.43-7.35(m, 2H), 7.30 (t, J = 7.7 Hz, 1H), 6.84 (dd, J = 16.7, 10.6 Hz, 1H),6.29 (dd, J = 16.7, 2.0 Hz, 1H), 5.80 (dd, J = 10.6, 2.0 Hz, 1H),5.43-5.29 (m, 1H), 4.86- 4.49 (br s, 2H), 4.33 (d, J = 13.7 Hz, 1H),4.26 611.2 (d, J = 13.5 Hz, 1H), 3.72 (t, J = 9.2 Hz, 1H), 3.61 (dd, J =9.2, 4.8 Hz, 1H), 3.48 (dd, J = 13.5, 4.7 Hz, 1H), 3.45-3.33 (m, 2H),3.39 (s, 3H), 3.14 (dd, J = 13.6, 2.9 Hz, 1H), 1.58 (d, J = 6.7 Hz, 3H),1.42 (d, J = 6.9 Hz, 3H). 2074

7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-10-(3,4-dichlorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one ¹H NMR (400 MHz, CDCl₃) δ 8.05(s, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.10- 7.07 (m, 1H),6.65-6.59 (m, 1H), 6.41 (dd, J = 1.6 Hz, 16.4 Hz, 1H), 5.77 (dd, J = 2.0Hz, 10.4 Hz, 1H), 5.45-5.42 (m, 1H), 4.68-4.66 (m, 1H), 4.17 (t, J =12.0 Hz, 627.3 2H), 3.69-3.63 (m, 2H), 3.40 (d, J = 8.0 Hz, 4H),3.37-3.30 (m, 3H), 2.99- 2.94 (m, 1H), 1.62-1.60 (m, 3H), 1.48-1.45 (m,3H). 2075

(3S,11S)-8-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- (pyridazin-3-yloxy)-10-(trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl₃) δ 8.90-8.83 (m, 1H), 8.10(s, 1H), 7.41 (dd, J = 4.4, 8.8 Hz, 1H), 7.32-7.27 (m, 1H), 7.07 (t, J =8.8 Hz, 1H), 7.02 (dd, J = 1.2, 8.8 Hz, 1H), 6.68-6.59 (m, 1H), 6.43(dd, J = 2.0, 16.8 Hz, 1H), 5.88-5.75 (m, 2H), 4.92-4.84 (m, 1H), 4.72(dd, J = 5.2, 10.0 Hz, 3H), 4.22 (br t, J = 693.0 11.6 Hz, 2H),3.51-3.29 (m, 3H), 3.22 (dd, J = 2.8, 13.6 Hz, 1H), 1.63-1.61 (m, 3H),1.52 (d, J = 7.2 Hz, 3H) 2076

(3S,11R)-8-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- (pyridazin-3-yloxy)-10-(trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one 1H NMR (400 MHz, CDCl₃) δ 8.86 (d, J = 4.4 Hz, 1H),8.12 (s, 1H), 7.4 (dd, J = 4.4, 8.8 Hz, 1H), 7.31- 7.28 (m, 1H), 7.05(t, J = 8.8 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.69-6.58 (m, 1H), 6.47-6.38 (m, 1H), 5.90-5.76 (m, 2H), 4.89 (dd, J = 8.0, 10.4 Hz, 1H), 4.71(dd, J = 5.2, 10.4 Hz, 3H), 4.28-4.15 693.0 (m, 2H), 3.48- 3.31 (m, 3H),3.20 (dd, J = 2.8, 13.6 Hz, 1H), 1.62 (s, 3H), 1.52 (d, J = 7.2 Hz, 3H)2077

(3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-10-(5-bromo-2-fluorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2,3- dihydro-5H-[1,4]thiazepino[2,3,4- ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ8.15 (s, 1H), 7.78-7.65 (m, 1H), 7.46 (ddd, J = 19.1, 6.4, 2.5 Hz, 1H),7.23 (td, J = 8.9, 3.9 Hz, 1H), 6.84 (dd, J = 16.7, 10.6 Hz, 1H), 6.29(dd, J = 16.6, 2.0 Hz, 1H), 5.80 (dd, J = 10.5, 2.0 Hz, 1H), 5.45-5.29(m, 1H), 4.86- 655.1 4.52 (br s, 2H), 4.34 (t, J = 11.3 Hz, 1H), 4.26(d, J = 13.6 Hz, 1H), 3.72 (dt, J = 18.8, 9.2 Hz, 1H), 3.66-3.56 (m,1H), 3.55- 3.46 (m, 1H), 3.45-3.33 (m, 2H), 3.40 (d, J = 6.3 Hz, 3H),3.21-3.09 (m, 1H), 1.63-1.51 (m, 3H), 1.42 (d, J = 7.0 Hz, 3H). 2078

(S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-10-(3-chlorophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2,3-J =dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one ¹H NMR (400 MHz,CDCl₃) δ 8.06 (s, 1H), 7.48-7.40 (m, 2H), 7.25-7.22 (m, 1H), 7.12 (t,7.2 Hz, 1H), 6.66-6.59 (m, 1H), 6.40 (dd, J = 1.6 Hz, 16.4 Hz, 1H), 5.77(dd, J = 2.0 Hz, 10.4 Hz, 1H), 5.44-5.41 (m, 1H), 4.77-4.57 (m, 2H),4.21- 4.16 (m, 2H), 593.1 3.71-3.61 (m, 2H), 3.41-3.30 (m, 6H), 2.99-2.94 (m, 1H), 1.62 (dd, J = 1.6 Hz, 6.8 Hz, 3H), 1.49-1.46 (m, 3H). 2079

(S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-10-(3-bromophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ8.13 (s, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.50-7.37 (m, 2H), 7.25 (dd, J =15.8, 7.7 Hz, 1H), 6.84 (dd, J = 16.7, 10.6 Hz, 1H), 6.29 (dd, J = 16.6,2.0 Hz, 1H), 5.80 (dd, J = 10.5, 2.0 Hz, 1H), 5.41-5.28 (m, 1H), 4.86-4.48 (br s, 2H), 637.1 4.34 (d, J = 13.7 Hz, 1H), 4.26 (d, J = 13.5 Hz,1H), 3.74 (dt, J = 11.2, 9.2 Hz, 1H), 3.61 (dt, J = 9.1, 4.5 Hz, 1H),3.49 (dd, J = 13.6, 4.7 Hz, 1H), 3.46-3.32 (m, 2H), 3.4 (d, J = 6.6 Hz,3H), 3.10 (ddd, J = 13.7, 5.4, 3.1 Hz, 1H), 1.57 (d, J = 6.9 Hz, 3H),1.42 (d, J = 6.9 Hz, 3H). 2080

(S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-10-(3-iodophenyl)-3- (methoxymethyl)-9- (trifluoromethyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ8.13 (s, 1H), 7.86 (d, J = 7.1 Hz, 1H), 7.63 (d, J = 13.9 Hz, 1H), 7.35-7.21 (m, 2H), 6.84 (dd, J = 16.6, 10.6 Hz, 1H), 6.29 (dd, J = 16.7, 2.0Hz, 1H), 5.80 (dd, J = 10.6, 2.0 Hz, 1H), 5.40-5.28 (m, 1H), 4.87- 4.50(br s, 2H), 685.1 4.34 (d, J = 13.7 Hz, 1H), 4.26 (d, J = 13.5 Hz, 1H),3.74 (dt, J = 12.7, 9.2 Hz, 1H), 3.61 (dt, J = 9.5, 5.0 Hz, 1H), 3.49(dd, J = 13.6, 4.7 Hz, 1H), 3.45-3.33 (m, 2H), 3.4 (d, J = 8.4 Hz, 1H),3.09 (ddd, J = 13.6, 7.0, 3.0 Hz, 1H), 1.57 (d, J = 6.9 Hz, 3H), 1.42(d, J = 6.9 Hz, 3H). 2081

(3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-10-(2-cyclopropylphenyl)- 3-(methoxymethyl)- 9-(trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4- ij]quinazolin-5-one ¹H NMR (400MHz, MeOH- d₄) δ 8.16 (s, 1H), 7.38 (t, J = 7.7 Hz, 1H), 7.24 (t, J =7.5 Hz, 1H), 7.04 (dd, J = 7.8, 4.3 Hz, 1H), 6.96 (t, J = 7.1 Hz, 1H),6.84 (dd, J = 16.6, 10.6 Hz, 1H), 6.29 (d, J = 16.6 Hz, 1H), 5.80 (d, J= 10.6 Hz, 1H), 5.42- 5.28 (m, 1H), 4.86-4.44 (br s, 599.3 2H),4.42-4.30 (m, 1H), 4.27 (dd, J = 13.7, 2.2 Hz, 1H), 3.79-3.65 (m, 1H),3.65-3.53 (m, 1H), 3.52- 3.43 (m, 1H), 3.43-3.35 (m, 1H), 3.38 (s, 3H),3.34-3.26 (m, 1H), 3.10 (td, J = 14.4, 13.7, 2.9 Hz, 1H), 1.59 (d, J =6.9 Hz, 3H), 1.48-1.33 (m, 4H), 0.86-0.65 (m, 3H). 2082

8′-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1- yl)-11′-(5-chloro-2,4-difluorophenyl)-3,3- difluoro-10′- (trifluoromethyl)- 2′H,4′H,6′H-spiro[cyclobutane- 1,3′- [1,4]thiazepino[2,3,4- ij]quinazolin]-6′-one ¹HNMR (400 MHz, MeOH- d₄) δ 7.96 (s, 1H), 7.61-7.41 (m, 1H), 7.34 (td, J =9.2, 3.7 Hz, 1H), 6.92- 6.71 (m, 1H), 6.37-6.21 (m, 1H), 5.81 (ddd, J =9.9, 7.2, 1.9 Hz, 1H), 4.87- 4.38 (m, 4H), 4.37-3.33 (m, 10H), 2.60-2.37(m, 2H), 1.59- 1.20 (m, 6H); 675.2 2083

8′-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-11′-(2,4-difluoro-5-iodophenyl)-10′- (trifluoromethyl)- 2′H,4′H,6′H- spiro[cyclobutane-1,3′- [1,4]thiazepino[2,3,4- ij]quinazolin]-6′-one ¹H NMR (400 MHz,MeOH- d₄) δ 8.12 (s, 1H), 7.83-7.67 (m, 1H), 7.21 (t, J = 8.7 Hz, 1H),6.84 (dd, J = 16.7, 10.6 Hz, 1H), 6.29 (dd, J = 16.7, 1.9 Hz, 1H), 5.80(dd, J = 10.6, 2.0 Hz, 1H), 4.86-4.37 (m, 4H), 4.24 (d, J = 13.5 Hz,2H), 3.50-3.36 (m, 3H), 3.30- 3.18 (m, 1H), 2.08-1.75 (m, 5H), 1.70-1.37731.1 (m, 6H). 2084

(S)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-3-(4-fluorophenoxy)-11- (4-fluorophenyl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4- ij]quinazolin-6-one ¹H NMR (400MHz, CDCl₃) δ 8.09 (s, 1H), 7.26-7.24 (m, 1H), 7.20-7.16 (m, 3H), 7.00-6.93 (m, 4H), 6.66-6.60 (m, 1H), 6.42 (dd, J = 16.4 Hz, 1.6 Hz, 1H),5.78 (dd, J = 10.4 Hz, 2.0 Hz, 1H), 4.96-4.60 (m, 5H), 4.18 (d, J = 13.2Hz, 2H), 3.43-3.35 (m, 3H), 3.17-3.13 (m, 1H), 1.55 (d, J = 6.8 Hz, 3H),1.53 (d, J = 657.2 6.4 Hz, 3H). 2085

(S)-8-((3R,5S)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-11-(3-chlorophenyl)-3-(4- fluorophenoxy)-10- (trifluoromethyl)-3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4- ij]quinazolin-6-one ¹H NMR (400MHz, CDCl₃) δ 8.09 (s, 1H), 7.48-7.43 (m, 2H), 7.28-7.26 (m, 1H), 7.18-7.10 (m, 1H), 6.99-6.94 (m, 4H), 6.66-6.59 (m, 1H), 6.42 (dd, J = 15.6Hz, 1.6 Hz, 1H), 5.78 (dd, J = 10.4 Hz, 2.0 Hz, 1H), 4.96-4.6 (m, 5H),4.18 (d, J = 13.2 Hz, 2H), 3.42-3.35 (m, 3H), 3.19- 3.15 (m, 1H),1.54-1.53 (m, 673.1 6H). 2086

(3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-10-(7-fluorobenzo[b]thio- phen-4-yl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazepino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.48 (d, J =5.6 Hz, 1H), 7.18 (d, J = 7.2 Hz, 2H), 6.79-6.77 (m, 1H), 6.66- 6.60 (m,1H), 6.41 (dd, J = 1.6 Hz, 16.8 Hz, 1H), 5.78 (dd, J = 2.0 Hz, 10.4 Hz,1H), 5.47- 5.42 (m, 1H), 4.87-4.46 (m, 2H), 4.24-4.21 (m, 2H), 3.64-3.57 (m, 2H), 633.2 3.43-3.33 (m, 5H), 3.23 (dd, J = 2.8 Hz, 13.6 Hz,1H), 2.97 (dd, J = 3.2 Hz, 13.6 Hz, 1H), 1.64 (d, J = 6.8 Hz, 3H), 1.48(d, J = 7.2 Hz, 3H). 2087

(3S,10S)-7-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1- yl)-10-(7-fluorobenzo[b]thio- phen-4-yl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.48 (d, J =5.6 Hz, 1H), 7.18- 7,16 (m, 2H), 6.80-6.77 (m, 1H), 6.66-6.60 (m, 1H),6.41 (dd, J = 2.0 Hz, 16.8 Hz, 1H), 5.78 (dd, J = 2.0 Hz, 10.4 Hz, 1H),5.47-5.39 (m, 1H), 4.89- 4.49 (m, 2H), 4.22-4.19 (m, 2H), 3.69-3.6 (m,2H), 3.44- 3.34 (m, 5H), 3.24 (dd, J = 3.2 Hz, 13.2 Hz, 1H), 2.92 (dd, J= 2.4 Hz, 13.6 Hz, 1H), 1.63 (d, J = 7.2 Hz, 3H), 1.49 (d, J = 6.8 Hz,3H). 2088

8′-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-11′-phenyl-10′-(trifluoromethyl)- 2,′H,4′H,6′H- spiro[cyclobutane- 1,3′-[1,4]thiazepino[2,3,4- ij]quinazolin]-6′-one ¹H NMR (400 MHz, MeOH- d₄)δ 8.11 (s, 1H), 7.52-7.41 (m, 3H), 7.33- 7.14 (m, 2H), 6.84 (dd, J =16.7, 10.6 Hz, 1H), 6.29 (dd, J = 16.7, 1.9 Hz, 1H), 5.80 (dd, J = 10.7,1.9 Hz, 1H), 4.86-4.4 (m, 4H), 4.25 (d, J = 13.5 Hz, 2H), 3.39 (dd, J =13.8, 4.6 Hz, 2H), 3.27-3.00 (m, 2H), 2.09- 1.72 (m, 5H), 569.31.67-1.36 (m, 6H). 2089

(3S,11R)-8-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3-(4- fluorophenoxy)-10-(trifluoromethyl)-3,4- dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.31-7.27(m, 1H), 7.06-7.01 (m, 1H), 7.04- 6.94 (m 4H), 6.66-6.59 (dd, J = 16.4Hz, 10.4 Hz, 1H), 6.44- 6.39 (dd, J = 16.4 Hz, 2.0 Hz, 1H), 5.80-5.77(dd, J = 10.4 Hz, 1.6 Hz, 1H), 5.00-4.63 (m, 5H), 4.17 (d, J = 13.2 Hz,2H), 3.52 (d, J = 15.6 Hz, 1H), 3.43- 3.36 (m, 2H), 709.2 3.22 (d, J =16.0 Hz, 1H), 1.56- 1.52 (m, 6H). 2090

(3S)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3-(4- fluorophenoxy)-10-(trifluoromethyl)-3,4- dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl₃) δ 8.11 (s, 1H), 7.26-7.23(m, 1H), 7.09-7.05 (t, J = 8.8 Hz 1H), 6.99-6.97 (m, 4H), 6.66- 6.59(dd, J = 16.8 Hz, 10.8 1H), 6.43- 6.39 (dd, J = 16.8 Hz, 1.6 Hz, 1H),5.80-5.77 (dd, J = 10.4 Hz, 1.6 Hz, 1H), 5.09-4.34 (m, 5H), 4.17 (d, J =13.2 Hz, 2H), 3.43-3.36 (m, 3H), 3.26-3.18 709.2 (m, 1H), 1.56- 1.52 (m,6H). 2091

(3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(4,5-dichloro- 2-fluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.36 (dd, J= 1.6 Hz, 8.4 Hz, 1H), 7.30 (d, J = 6.8 Hz, 1H), 6.65-6.59 (m, 1H), 6.41(dd, J = 1.6 Hz, 16.8 Hz, 1H), 5.77 (dd, J = 1.6 Hz, 10.4 Hz, 1H),5.46-5.42 (m, 1H), 4.72-4.57 (m, 2H), 4.18 (t, J = 11.2 Hz, 2H),3.66-3.61 645.1 (m, 2H), 3.41- 3.30 (m, 6H), 3.05-3.00 (m, 1H), 1.61 (d,J = 7.2 Hz, 3H), 1.48-1.45 (m, 3H). 2092

(3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(2-fluoro-4- methylphenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ 8.13 (s, 1H), 7.18-7.02(m, 3H), 6.84 (dd, J = 16.7, 10.6 Hz, 1H), 6.29 (dd, J = 16.7, 1.9 Hz,1H), 5.80 (dd, J = 10.6, 2.0 Hz, 1H), 5.42-5.28 (m, 1H), 4.87- 4.46 (brs, 2H), 4.33 (dd, J = 13.7, 5.6 Hz, 1H), 4.25 (d, J = 591.3 13.6 Hz,1H), 3.71 (td, J = 9.2, 5.6 Hz, 1H), 3.59 (dt, J = 9.6, 5.1 Hz, 1H),3.47 (ddd, J = 13.4, 8.5, 4.7 Hz, 1H), 3.42- 3.33 (m, 1H), 3.39 (s, 3H),3.13 (dt, J = 13.7, 3.2 Hz, 1H), 2.45 (s, 3H), 1.58 (dd, J = 7.1, 3.4Hz, 3H), 1.42 (d, J = 6.9 Hz, 3H). 2093

8′-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-11′-(2-cyclopropylphenyl)- 10′-(trifluoromethyl)- 2′H,4′H,6′H-spiro[cyclobutane- 1,3- [1,4]thiazepino[2,3,4- ij]quinazolin]-6′-one ¹HNMR (400 MHz, MeOH- d₄) δ 8.14 (s, 1H), 7.35 (t, J = 6.6 Hz, 1H), 7.22(t, J = 7.5 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H),6.84 (dd, J = 16.7, 10.6 Hz, 1H), 6.29 (dd, J = 16.7, 2.0 Hz, 1H), 5.80(dd, J = 10.6, 2.0 Hz, 1H), 4.85-4.38 (m, 5H), 4.35- 4.13 (m, 2H), 3.39(dd, J = 609.3 13.7, 4.6 Hz, 2H), 3.27-3.0 (m, 2H), 2.18- 1.72 (m, 5H),1.68-1.32 (m, 6H), 0.89-0.62 (m, 4H). 2094

(3S,11S)-8-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-bromo-2,4- difluorophenyl)-3- (pyrimidin-2-yloxy)-10-(trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 4.8 Hz, 2H),8.10 (s, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.07-6.96 (m, 2H), 6.64 (dd, J =10.4, 16.8 Hz, 1H), 6.48-6.38 (m, 1H), 5.86- 5.68 (m, 2H), 5.18-4.42 (m,4H), 4.21-4.14 (m, 2H), 3.61- 3.34 (m, 4H), 1.56-1.53 (m, 6H) 739.2 2095

(3S,11R)-8-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-bromo-2,4- difluorophenyl)-3- (pyrimidin-2-yloxy)-10-(trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 4.8 Hz, 2H),8.10 (s, 1H), 7.49- 7.30 (m, 1H), 7.05 (t, J = 8.4 Hz, 1H), 6.99 (t, J =4.8 Hz, 1H), 6.69-6.57 (m, 1H), 6.42 (dd, J = 2.0, 16.8 Hz, 1H),5.84-5.58 (m, 2H), 5.18- 4.42 (m, 4H), 4.23-4.09 (m, 2H), 3.67-3.25 (m,4H), 1.57- 1.48 (m, 6H) 739.2 2096

8′-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-11′-(2,4-difluorophenyl)-10′- (trifluoromethyl)- 2′H,4′H,6′H- spiro[cyclobutane-1,3′- [1,4]thiazepino[2,3,4- ij]quinazolin]-6′-one ¹H NMR (400 MHz,MeOH- d₄) δ 8.13 (s, 1H), 7.39-7.23 (m, 1H), 7.18- 7.04 (m, 2H), 6.84(dd, J = 16.7, 10.6 Hz, 1H), 6.29 (dd, J = 16.7, 2.1 Hz, 1H), 5.80 (dd,J = 10.5, 2.1 Hz, 1H), 4.87-4.37 (m, 4H), 4.24 (d, J = 13.5 Hz, 2H),3.50-3.33 (m, 3H), 3.29- 3.14 (m, 1H), 2.15-1.74 (m, 6H), 1.69-1.35605.2 (m, 6H). 2097

(3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(4,5-dichloro- 2-fluorophenyl)-3- (methoxymethyl)-9-(trffluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, CDCl3) δ ppm 0.48-0.74 (m, 4H) 1.55(br s, 6H) 3.17 (br d, J = 15.0 Hz, 1H) 3.21- 3.65 (m, 4H) 4.00-4.54 (m,4H) 4.56-4.90 (m, 3H) 5.79 (dd, J = 10.4, 2.0 Hz, 1H) 6.42 (dd, J =16.8, 2.0 Hz, 1H) 6.63 (dd, J = 16.8, 10.4 Hz, 1H) 7.05 (t, J = 8.8 Hz,1H) 7.26 (br s, 1H) 655.2 8.08 (s, 1H) 2098

(3S,10R)-7-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-10-(4,5-dichloro- 2-fluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.36 (d, J =8.4 Hz, 1H),7.31 (d, J = 6.8 Hz, 1H), 6.66-6.59 (m, 1H), 6.41 (dd, J =2.0 Hz, 16.8 Hz, 1H), 5.77 (dd, J = 1.6 Hz, 10.4 Hz, 1H), 5.47-5.42 (m,1H), 4.76-4.53 (m, 2H), 4.21- 4.15 (m, 2H), 3.66-3.64 (m, 645.1 2H),3.41-3.30 (m, 6H), 3.05- 3.01 (m, 1H), 1.61 (d, J = 6.8 Hz, 3H), 1.48(d, J = 7.2 Hz, 3H). 2099

(3S,10S)-7-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-10-(4,5-dichloro- 2-fluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.36 (d, J =8.0 Hz, 1H),7.30 (d, J = 6.8 Hz, 1H), 6.66-6.59 (m, 1H), 6.41 (dd, J =2.0 Hz, 17.2 Hz, 1H), 5.78 (dd, J = 2.0 Hz, 10.4 Hz, 1H), 5.48-5.44 (m,1H), 4.71-4.62 (m, 2H), 4.21- 4.16 (m, 2H), 3.67-3.62 (m, 645.1 2H),3.39-3.30 (m, 6H), 3.04- 3.00 (m, 1H), 1.61 (d, J = 6.8 Hz, 3H), 1.46(d, J = 6.8 Hz, 3H). 2100

(3S,11S)-7-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-10-(4,5-dichloro- 2-fluorophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one ¹H NMR (400 MHz, CDCl3) δ ppm 0.52-0.71 (m, 4H)1.48- 1.58 (m, 6H) 3.17 (br d, J = 14.8 Hz, 1H) 3.26-3.55 (m, 4H)4.08-4.46 (m, 4H) 4.54- 4.87 (m, 3H) 5.79 (dd, J = 10.4, 2.0 Hz, 1H)6.42 (dd, J = 16.8, 2.0 Hz, 1H) 6.63 (dd, J = 16.8, 10.4 Hz, 1H) H) 7.05(t, J = 8.8 Hz, 1H) 7.29 (br s, 1H) 655.2 8.07 (s, 1H) 2101

(3S)-8-((3S,5R)-4- Acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4- difluorophenyl)-3- cyclopropoxy-10-(trifluoromethyl)-3,4- dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one ¹H NMR (400 MHz, CDCl3) δ ppm 0.51-0.77 (m, 4H) 1.55(br s, 6H) 3.10- 3.59 (m, 5H) 3.97-4.52 (m, 4H) 4.55-4.97 (m, 3H) 5.72-5.87 (m, 1H) 6.42 (dd, J = 16.8, 2.0 Hz, 1H) 6.63 (dd, J = 16.8, 10.4Hz, 1H) 7.06 (t, J = 8.8 Hz, 1H) 7.22-7.27 (m, 1H) 8.08 (s, 1H) H) 655.22102

(3S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(2-fluoro-5- iodophenyl)-3- (methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one 1H NMR (400 MHz, MeOH- d₄) δ 8.14 (s, 1H), 7.93-7.83(m, 1H), 7.61 (ddd, J = 16.3, 6.7, 2.2 Hz, 1H), 7.09 (td, J = 9.0, 4.1Hz, 1H), 6.84 (dd, J = 16.7, 10.6 Hz, 1H), 6.29 (dd, J = 16.7, 1.9 Hz,1H), 5.80 (dd, J = 10.6, 1.9 Hz, 1H), 5.43-5.27 (m, 1H), 4.87- 703.04.46 (br s, 2H), 4.42-4.30 (m, 1H), 4.26 (d, J = 13.6 Hz, 1H), 3.72 (dt,J = 20.7, 9.2 Hz, 1H), 3.61 (td, J = 9.5, 4.8 Hz, 1H), 3.49 (ddd, J =13.4, 11.3, 4.7 Hz, 1H), 3.45-3.33 (m, 2H), 3.40 (d, J = 8.1 Hz, 4H),3.15 (ddd, J = 13.7, 8.3, 3.0 Hz, 1H), 1.57 (dd, J = 7.0, 3.3 Hz, 3H),1.42 (d, J = 6.9 Hz, 3H). 2103

8′-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1- yl)-11′-(2,4-difluoro-5-iodophenyl)-10′- (trifluoromethyl)- 2′H,4′H,6′H- spiro[cyclobutane-1,3′- [1,4]thiazepino[2,3,4- ij]quinazolin]-6′-one ¹H NMR (400 MHz,MeOH- d₄) δ 7.92 (s, 1H), 7.83-7.63 (m, 1H), 7.21 (td, J = 8.8, 3.5 Hz,1H), 6.93- 6.70 (m, 1H), 6.28 (dd, J = 16.8, 5.5 Hz, 1H), 5.89-5.74 (m,1H), 4.87- 4.03 (m, 5H), 3.97-3.64 (m, 2H), 3.49-3.33 (m, 1H), 3.29-3.10 (m, 1H), 2.16-1.74 (m, 6H), 1.61-1.13 (m, 6H). 731.1 2104

(S)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1- yl)-3-(methoxymethyl)-10- (phenyl-d₅)-9- (trifluoromethyl)-2,3- dihydro-5H-[1,4]thiazino[2,3,4- ij]quinazolin-5-one ¹H NMR (400 MHz, MeOH- d₄) δ8.13 (s, 1H), 6.84 (dd, J = 16.6, 10.6 Hz, 1H), 6.29 (dd, J = 16.7, 1.9Hz, 1H), 5.80 (dd, J = 10.6, 1.9 Hz, 1H), 5.40-5.27 (m, 1H), 4.85- 4.47(br s, 2H), 4.34 (d, J = 13.7 Hz, 1H), 4.26 (d, J = 13.5 Hz, 1H), 3.73(t, J = 9.2 Hz, 1H), 3.60 (dd, J = 9.2, 4.7 Hz, 564.2 1H), 3.47 (dd, J =13.5, 4.7 Hz, 1H), 3.42-3.34 (m, 1H), 3.39 (s, 3H), 3.28 (d, J = 3.1 Hz,1H), 3.08 (dd, J = 13.7, 2.9 Hz, 1H), 1.58 (d, J = 6.9 Hz, 3H), 1.42 (d,J = 6.9 Hz, 3H). 2105

(S)-8′-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11′-(2,4-difluoro- 5-iodophenyl)-10′- (trifluoromethyl)-2′H,4′H,6′H- spiro[cyclobutane- 1,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one ¹H NMR (400 MHz, MeOH- d₄) δ 8.12 (s, 1H),7.82-7.67 (m, 1H), 7.21 (t, J = 8.7 Hz, 1H), 6.84 (dd, J = 16.7, 10.6Hz, 1H), 6.29 (dd, J = 16.7, 2.0 Hz, 1H), 5.80 (dd, J = 10.6, 2.0 Hz,1H), 4.88-4.38 (m, 4H), 4.24 (d, J = 13.5 Hz, 2H), 3.51-3.34 (m, 3H),3.29- 3.13 (m, 1H), 2.15-1.70 (m, 6H), 1.68-1.39 731.1 (m, 6H). 2105

(R)-8′-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11′-(2,4-difluoro- 5-iodophenyl)-10′- (trifluoromethyl)-2′H,4′H,6′H- spiro[cyclobutane- 1,3′- [1,4]thiazepino[2,3,4-ij]quinazolin]-6′-one ¹H NMR (400 MHz, MeOH- d₄) δ 8.12 (s, 1H),7.82-7.67 (m, 1H), 7.21 (t, J = 8.7 Hz, 1H), 6.84 (dd, J = 16.7, 10.6Hz, 1H), 6.29 (dd, J = 16.7, 2.0 Hz, 1H), 5.80 (dd, J = 10.5, 2.0 Hz,1H), 4.88-4.38 (m, 4H), 4.24 (d, J = 13.5 Hz, 2H), 3.49-3.33 (m, 3H),3.29- 3.13 (m, 1H), 2.13-1.73 (m, 6H), 1.69-1.38 731.1 (m, 6H). 2106

8′-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1- yl)-11′-(2,4-difluorophenyl)-10′- (trifluoromethyl)- 2′H,4′H,6′H- spiro[cyclobutane-1,3- [1,4]thiazepino[2,3,4- ij]quinazolin]-6′-one ¹H NMR (400 MHz, MeOH-d₄) δ 7.93 (s, 1H), 7.40-7.23 (m, 1H), 7.18- 7.04 (m, 2H), 6.93-6.70 (m,1H), 6.28 (dd, J = 16.5, 6.0 Hz, 1H), 5.88-5.72 (m, 1H), 4.88- 4.15 (m,5H), 4.00-3.68 (m, 2H), 3.54-3.34 (m, 1H), 3.29- 3.09 (m, 1H), 2.13-1.74(m, 5H), 1.55-1.18 (m, 6H). 605.2 2107

(3S)-8-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-11-(2,4-difluoro- 5-iodophenyl)-3- (pyrimidin-2-yloxy)-10-(trifluoromethyl)- 3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one 1H NMR (400 MHz, CDCl₃) δ = 8.52 (d, J = 4.0, 2H),8.09 (s, 1H), 7.60-7.52 (m, 1H), 7.00- 6.90 (m, 2H), 6.63 (dd, J = 16.4,10.4, 1H), 6.40 (d, J = 16.0, 1H), 5.7 8 (d, J = 10.0, 1H), 5.75 (bs(1H), 4.92-4.50 (m, 4H), 4.19- 4.15 (m, 2H), 3.60-3.25 (m, 4H), 1.58(bs, 3H), 1.45 (bs, 785.0 3H). 2108

(3S,10R)-7-((3S,5R)-4- acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-bromo-2,4- difluorophenyl)-3- ethyl-9- (trifluoromethyl)-2,3-dihydro-5H- [1,41thiazino[2,3,4- ijlquinazolin-5-one ¹H NMR (400 MHz,MeOH- d₄) δ 8.15 (s, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.34 (t, J = 8.9 Hz,1H), 6.84 (dd, J = 16.7, 10.6 Hz, 1H), 6.29 (dd, J = 16.6, 1.9 Hz, 1H),5.80 (dd, J = 10.7, 2.0 Hz, 1H), 5.18-5.05 (m, 1H), 4.86- 4.52 (br s,2H), 4.28 (dd, J = 23.1, 13.5 Hz, 657.1 2H), 3.44 (ddd, J = 24.4, 13.5,4.6 Hz, 2H), 3.35-3.25 (m, 2H), 3.16 (dd, J = 13.9, 2.9 Hz, 1H), 1.57(d, J = 6.7 Hz, 3H), 1.43 (d, J = 6.9 Hz, 3H). 2109

8′-((2S,5R)-4- acryloyl-2,5- dimethylpiperazin-1- yl)-11′-(5-bromo-2,4-difluorophenyl)-10′- (trifluoromethyl)- 2′H,4′1,6′H- spiro[oxetane-3,3′-[1,4]thiazepino[2,3,4- ij]quinazolin]-6′-one ¹H NMR (400 MHz, MeOH- d₄)δ 7.96 (s, 1H), 7.71-7.51 (m, 1H), 7.31 (td, J = 9.0, 3.3 Hz, 1H), 6.91-6.70 (m, 1H), 6.35-6.20 (m, 1H), 5.87-5.72 (m, 1H), 4.88- 4.56 (m, 4H),4.55-4.37 (m, 3H), 4.36-4.01 (m, 2H), 4.00- 3.35 (m, 5H), 1.43 (dd, J =16.2, 6.5 Hz, 3H), 1.38-1.23 (m, 3H). 685.0 2110

(3S,10S)-7-((3S,5R)- 4-acryloyl-3,5- dimethylpiperazin-1-yl)-10-(5-bromo-2,4- difluorophenyl)-3- ethyl-9- (trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazepino[2,3,4- ij]quinazolin-5-one 1H NMR (400 MHz,MeOH- d₄) δ 8.15 (s, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 8.9 Hz,1H), 6.84 (dd, J = 16.7, 10.6 Hz, 1H), 6.29 (dd, J = 16.6, 2.0 Hz, 1H),5.80 (dd, J = 10.6, 2.0 Hz, 1H), 5.20-5.06 (m, 1H), 4.86- 4.53 (br s,2H), 4.30 (dd, J = 31.5, 13.6 Hz, 657.1 2H), 3.46 (ddd, J = 32.4, 13.6,4.7 Hz, 2H), 3.36-3.24 (m, 2H), 3.18 (dd, J = 13.9, 2.9 Hz, 1H), 1.57(d, J = 7.0 Hz, 3H), 1.42 (d, J = 6.9 Hz, 3H).

In certain embodiments, compounds of the various embodiments disclosedherein may be:

AA. Example 7 CAF Assay

This Example provides a protocol for assessing covalent adduct formation(CAF) between the compounds of the present application and KRAS.

In vitro covalent adduct formation assay: Covalent adduct formation(CAF) reactions between Cys12 of the KRAS 4B G12C protein and some ofthe compounds of Tables 1 to 4 were measured in vitro using liquidchromatography-mass spectrometry (LC-MS).

Recombinant Human KRAS 4B protein containing the G12C mutation was usedin compound screening experiments. This protein contained 188 aminoacids in total, including an N-terminal 6-Histidine tag, followed by aTobacco Etch Virus (TEV) tag, followed by residues 1-169 of the nativeKRAS 4B sequence. The exact mass of the protein was 21,310 Da asdetermined by mass spectrometry. The full amino acid sequence is shownbelow:

(SEQ ID NO.: 4)   MAHHHHHHAG GAENLYFQSM TEYKLVVVGA CGVGKSALTIQLIQNHFVDE YDPTIEDSYR KQVVIDGETC LLDILDTAGQEEYSAMRDQY MRTGEGFLCV FAINNTKSFE DIHHYREQIKRVKDSEDVPM VLVGNKCDLP SRTVDTKQAQ DLARSYGIPFIETSAKTRQG VDDAFYTLVR EIRKHKEK

In an alternative screen, the assay can be conducted using a KRAS 4bG12C protein having 170 amino acids, a mass of 19,336 Da, and the aminoacid sequence

(SEQ ID NO.: 5)   SMTEYKLVVVGA CGVGKSALTI QLIQNHFVDE YDPTIEDSYRKQVVIDGETC LLDILDTAGQ EEYSAMRDQY MRTGEGFLCVFAINNTKSFE DIHHYREQIK RVKDSEDVPM VLVGNKCDLPSRTVDTKQAQ DLARSYGIPF IETSAKTRQG VDDAFYTLVR EIRKHKEK.

The recombinant protein was expressed in E. coli BL21 cells and purifiedusing affinity chromatography via a Ni-NTA column. Protein stocks werenucleotide-exchanged to >95% GDP, concentrated to 4 mg/mL, and stored at−80° C. in storage buffer (50 mM HEPES pH 7.4, 50 mM NaCl, 5 mM MgCl2, 1mM DTT). Pure KRAS 4B G12C protein was diluted to a concentration of 5μM in Tris Buffered Saline, pH 7.4. The compounds were dissolved in DMSOand added to the diluted protein to make a 10 μM concentration. Thetotal DMSO concentration in the reaction was 4%. The reaction was mixedby pipetting and incubated at 22° C. for one hour. Aliquots of thereaction were taken over time and diluted 2:1 in 0.1% formic acid. Theintact mass of the protein samples was measured by LC-MS using aQExactive+ mass spectrometer (Thermo Scientific). An amount of 500 ngtotal protein was injected onto a C8 reverse phase column, eluted with aseven-minute gradient of 30%-90% acetonitrile/0.10% formic acid, andanalyzed for intact mass by the mass spectrometer. Adducts identifiedwere confirmed to be within 1 Dalton of the expected mass, and therelative ratios of free:adduct protein were used to quantify thepercentage of protein bound by the compound. CAF reactions were run induplicate, with a typical variability of ±5%.

BB. Example 9: Determination of Total Drug Concentration in Rat Brain

In Vivo Experimental Procedures

Infuse male SD rat at 2 mg/kg dose for 4 hours through IV administrationroute. Collect brain tissues at the end of 4 hours.

Sample Preparation Procedures

Dilute brain tissue by adding homogenization solvent (1:4, w/v).Homogenize diluted brain tissue samples. Extract analyte by addingorganic solvent (1:4, v/v) with spiked internal standard. Vortex andcentrifuge the samples. Remove supernatant and dilute with HPLCcompatible solvent (1:3, v/v).

Analytical Procedures

Inject diluted extract into LC-MS/MS system using reversed phase highperformance liquid chromatography coupled with electrospray ionizationand selected reaction monitoring. Determine the total drug concentrationin brain samples by quantitating against the standard curve preparedusing the same matrix.

The following data provides blood brain barrier (BBB) penetrationactivity for a selection of inventive compounds where were directlycompared to sotorasib and adagrasib (concentration in brain measured inng/g).

TABLE 13 BBB activity BBB Entry # Structure activity 13-1

+ 13-2

+ 13-3

+ 13-4

+ 13-5

+ 13-6

+ 13-7

+ 13-8

+ 13-9

+ 13-10

+ 13-12

+ 13-13

+ 13-14

+ 13-15

+ 13-16

+ 13-17

+ 13-18

+ 13-19

+ 13-20

+ 13-21

+ 13-22

+ 13-23

+ 13-24

+ 13-25

+ 13-26

+ 13-27

+ 13-28

+ 13-29

+ 13-30

+ 13-31

+ 13-32

+ 13-33

+ 13-34

+ 13-35

+ 13-36

+ 13-37

+ 13-38

+ 13-39

+ 13-40

+ 13-41

+ 13-42

+ 13-43

+ 13-44

+ 13-45

+ 13-46

+ 13-47

− 13-48

− 13-49

− 13-50

− 13-51

− 13-52

− 13-53

− 13-54

− 13-55

− 13-56

− 13-57

− 13-58

− 13-59

− 13-60

− 13-61

− 13-62

− 13-63

− 13-64

− 13-65

− 13-66

− 13-67

− 13-68

− 13-69

− 13-70

− 13-71

− 13-72

− 13-73

− 13-74

− 13-75

− 13-76

− 13-77

− 13-78

− 13-79

− 13-80

− 13-81

− 13-82

− 13-83

− 13-84

− 13-85

− 13-86

− 13-87

− 13-88

− 13-89

− 13-90

− 13-91

− 13-92

−

Compounds that were measured as having a total concentration in thebrain of at least 60 ng/g are indicated as “+”. Compounds that did notmeet this threshold are indicated as “−”. The data from the tableclearly indicates that the compounds have superior brain penetrationthan sotorasib and adagrasib, two clinical candidates.

Embodiments herein relate to methods of using compounds and classes ofcompounds described herein, including those set forth in Table 13, totreat CNS cancers, due at least in part, to the surprising brainpenetration capacity of the compounds. Those CNS cancers can includeany, including those described herein. The cancers can be RAS related insome embodiments. The cancers can be primary and/or secondary CNScancers, including those described herein. The compounds can serve toprevent or reduce metastatic spread via the CNS.

What is claimed is:
 1. A compound selected from:

or a pharmaceutically acceptable salt thereof.
 2. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 11. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 15. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 17. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 18. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 19. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 20. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 21. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 22. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 23. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 24. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 25. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 26. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 27. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 28. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 29. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 30. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.